Cupraelectro-Catalyzed Alkyne Annulation: Evidence for Distinct C-H Alkynylation and Decarboxylative C-H/C-C Manifolds

Article abstract of DOI:10.1021/acscatal.9b02348

Synthetically meaningful isoindolones were accessed by cupraelectro-catalyzed C-H activation with electricity as terminal oxidant. Thus, a versatile, inexpensive, and nontoxic Cu(OAc)₂ catalyst enabled broadly applicable C-H/N-H functionalizations on electron-rich and electron-deficient benzamides with distinct functional group tolerance and resource-economy. Detailed mechanistic studies provided strong support for a C-H alkynylation mechanism through fast C-H metalation, which likewise set the stage for cupraelectro-catalyzed C-H/C-C functionalizations in a decarboxylative fashion.

Full text of DOI:10.1021/acscatal.9b02348

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Article
Cupraelectro-Catalyzed Alkyne Annulation: Evidence for Distinct
C–H Alkynylation and Decarboxylative C–H/C–C Manifolds
Cong Tian, Uttam Dhawa, Alexej Scheremetjew, and Lutz Ackermann
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02348 • Publication Date (Web): 12 Jul 2019
Downloaded from pubs.acs.org on July 12, 2019
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ACS Catalysis
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Cupraelectro-Catalyzed Alkyne Annulation: Evidence for
Distinct C–H Alkynylation and Decarboxylative C–H/C–C
Manifolds
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Cong Tian,‡ Uttam Dhawa,‡ Alexej Scheremetjew, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077, Göttingen
(Germany).
Supporting Information Placeholder
ABSTRACT: Synthetically meaningful isoindolones were accessed by cupraelectro-catalyzed C–H activation with electricity as
terminal oxidant. Thus, a versatile, inexpensive and non-toxic Cu(OAc)2 catalyst enabled broadly applicable C–H/N–H
functionalizations on electron-rich and electron-deficient benzamides with distinct functional group tolerance and resource-economy.
Detailed mechanistic studies provided strong support for a C–H alkynylation mechanism through fast C–H metalation, which likewise
set the stage for cupraelectro-catalyzed C–H/C–C functionalizations in a decarboxylative fashion.
Keywords: alkynylation, annulation, copper, C–H activation, C–C cleavage, electrochemistry, isoindolone
metallaelectro-catalyzed C–H alkynylation delivered for the
first time bioactive five-membered isoindolones.17
INTRODUCTION
The effective conversion of renewable electricity into value-
added chemical products bears considerable potential towards a
sustainable energy economy.1 C–H activation has emerged as
an increasing powerful platform for molecular syntheses,2 with
transformative applications to late-stage diversification,3
material sciences,4a,b and pharmaceutical industries.4c,d In recent
years, merging oxidative C–H transformations with
electrocatalysis5 has significantly improved the sustainability of
3d-transition metal-catalyzed C–H activation,6 hence avoiding
the use of toxic and expensive stoichiometric oxidants. Thus,
very recent momentum was gained by electrocatalysis for inter
alia C–C,7 C–O,8 and C–N9 bond formations,10 with key
contribution by Xu,11 and Mei,12 among others. In this context,
Mei elegantly developed very recent copper-catalyzed
electrochemical aminations with electron-rich anilides, through
a proposed single electron transfer (SET) from the anilide
substrates.13 Despite indisputable advances, electrocatalyzed
C–H alkynylations14 have thus far generally proven elusive,
while cupraelectro-catalyzed C–H activations of electron-
deficient arenes are as of yet unprecedented. In sharp contrast,
within our program on sustainable C–H activation,15 we have
now developed the first copper-catalyzed electro-oxidative
alkyne annulation enabled by C–H alkynylations of
synthetically-valuable, inherently electron-deficient aromatic
amides (Figure 1). Notable features of our findings comprise 1)
unprecedented electro-oxidative annulations by C–H
alkynylations, 2) earth-abundant, non-toxic copper catalysts, 3)
user-friendly undivided cell set-up, 4) mechanistic insights into
O
Earth-abundant Cu
R
C–H Alkynylation
Electron-Deficient Arenes
Bioactive Isoindolones
Decarboxylative
C–H/C–C scission
Electricity as oxidant
H
N
H
O
H
O
R
N
Cu
N
R
H
O
R
N
H
toxic
oxidants
O
- CO2
OH
Figure 1. Cupraelectro-catalyzed C–H alkynylation.
RESULTS AND DISCUSSION
Optimization Studies. We initiated our studies by probing
various reaction conditions for the envisioned copper-catalyzed
electrooxidative C–H/N–H activation of benzamide 1a with
terminal alkyne 2a in an operationally-simple undivided cell
set-up (Table 1 and Table S1 in the Supporting Information).
After considerable preliminary experimentation, we observed
that the desired isoindolone 3aa was obtained by catalytic
amounts of Cu(OAc)2∙H2O, along with NaOPiv as the optimal
additive at 100 °C in DMA (entries 1-7). The addition of redox
mediators, such as TBAI and TEMPO, did not improve the
performance of the copper catalyst (entries 8-9). A reaction
conducted in a potentiostatic manifold at 2.0 V gave similar
results as was obtained for the galvanostatic regime (entry 10).
cupraelectro-catalyzed
decarboxylative C–H/C–C functionalizations by electro-
catalysis. It is noteworthy that in contrast to recent alkyne
C–H
alkynylations,
and
5)
annulations
for
six-membered
isoquinolones,16
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Control experiments revealed the essential role of the
electricity, the additive and the copper catalyst with a minor
influence of oxygen (entries 11-14). Notably, a set of typical
transition metal catalysts based on manganese, nickel,
ruthenium, rhodium, iridium and palladium fell short in
delivering any products (entries 15-20).
Page 2 of 9
RVC
Pt
O
H
1
2
3
4
O
H
R
Cu(OAc)2·H2O (5.0 mol %)
N
H
+
N
R
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
Ph
Ph
1
2a
3
5
6
O
O
O
O
Oxa
O
7
8
9
N
Table 1. Optimization of cupraelectro-catalyzed
isoindolone synthesis.a
N
Q
N
N
N
Ph
Ph
Ph
: 90% (E/Z = 1:13)
Ph
Ph
3aa
3ba
3ca
3da
: --
: 20%
: --
Pt
10
11
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RVC
O
O
H
Cu(OAc)2·H2O (5.0 mol %)
Oxa = 2-Oxazoline.
N
H
N
Q
+
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
N
H
Ph
Ph
Scheme 1. Effect of the N-substitution on the cupraelectro-
1a
2a
3aa
catalysis.
entry
1
deviation from standard condition
None
E/Z
1:13
1:6
1:4
1:1
–
yield [%]b
Versatility. With the optimized reaction conditions in hand,
we tested the versatility of our cupraelectro-catalyzed
annulation regime with diversely decorated benzamides 1
(Scheme 2). Electron-rich as well as electron-deficient arenes
1e-1n were both amenable to the cupraelectro-catalyzed C–H
alkynylation cascade, chemo-selectively providing the
corresponding isoindolinones 3. The positional selectivities for
meta-substituted arenes 1h and 1m were governed by steric
interactions. Notably, the sustainable copper catalyst tolerated
a diverse array of valuable electrophilic functional groups,
including thioether (3ra) and electron-withdrawing bromo
(3pa), iodo (3qa), nitro (3sa) and cyano (3ta) substituents,
which should prove invaluable for further late-stage
diversifications.
90
58
44
51
–
2
NaOAc instead of NaOPiv
Na2CO3 instead of NaOPiv
KOPiv instead of NaOPiv
tAmOH instead of DMA
DMF instead of DMA
NMP instead of DMA
TBAI (50 mol %) additive
TEMPO (20 mol %) additive
Constant potential at 2.0 V
No electricity
3
4
5
6
1:3
1:8
1:10
1:8
1:12
1:8
1:9
–
56
80
76
81
86
18
5
7
8
9
10
11
12
13
14
15
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17
18
19
20
No electricity, under N2
No Cu catalyst
–
No NaOPiv
–
–
Mn(OAc)2 as catalyst
Ni(OAc)2∙4H2O as catalyst
[RuCl2(p-cymene)]2 as catalyst
[Cp*RhCl2]2 as catalyst
[Cp*IrCl2]2 as catalyst
Pd(OAc)2 as catalyst
–
–
–
–
–
–
–
–
–
–
–
–
a General reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol),
Cu(OAc)2∙H2O (5.0 mol %), NaOPiv (1.0 equiv), DMA (4.0 mL),
100 °C, constant current at 6.0 mA, 6 h, RVC anode, Pt-plate
cathode, undivided cell. b Yield of isolated product. DMA = N,N-
Dimethylacetamide, DMF = N,N-Dimethylformamide, NMP = N-
Methyl-2-pyrrolidone. TBAI = Tetra-n-butylammonium iodide.
Subsequently, we evaluated the effect of the N-substitution-
pattern on the cupraelectro-catalyzed C–H/N–H annulation
(Scheme 1). Thus, either phenyl oxazoline 1b or pyridine-N-
oxide 1c proved to be ineffective in giving comparable yields
of the desired isoindolinone, as was also noted for the simple N-
phenylbenzamide 1d.
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RVC
Pt
RVC
Pt
O
H
O
H
O
O
H
H
R
Q
Cu(OAc)2·H2O (5.0 mol %)
Q
Cu(OAc)2·H2O (5.0 mol %)
N
H
N
H
+
+
N Q
N
Q
R
R
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
Ph
R
Ph
5
1a
2
3
1
2a
3
6
O
O
O
7
8
9
R
O
Br
O
O
N
Q
N
Q
N Q
Cl
N
Q
N
Q
N
Q
R
MeO
Ph
Ph
Ph
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3ae
3af
: 70% (E/Z = 1:4)
3ab
77% (E/Z = 1:6)
: 66% (E/Z = 1:4)
R = Me (
):
3aa
: 90% (E/Z = 1:13)
3ea
R = Me (
): 83% (E/Z = 1:10)
3ga
: 65% (E/Z = 1:10)
3ac 72% (E/Z = 1:1.4)
R = OMe (
):
R = Ph ( ): 51% (E/Z = 1:3)a
3fa
3ad
81% (E/Z = 1:16)
R = tBu (
):
O
O
O
H
O
O
O
Me
N
Q
N
Q
N Q
N
Q
N
Q
N
Q
O
R
tBu
R
S
OEt
3al
: 42% (E/Z = 1:5)
Ph
Ph
Ph
a
b
3ha
3ia
R = Me ( ): 72% (E/Z = 1:12)
3ka
: 56%
: 87% (E/Z = 1:13)
3ag
R = CF3
(
):
60% (E/Z = 1:20)
73% (E/Z = 1:6)
72% (E/Z = 1:4)
3ak
: 75% (E/Z = 1:3)
3ja
R = Ph ( ): 72% (E/Z = 1:8)
3ah
R = F (
):
3ai
R = Br ( ):
3aj
R = CO2Me ( ): 70% (E/Z = 1:7)
H
O
O
O
Me
O
N
Q
N
Q
N
Q
Me
F3C
N
Q
=
Ph
Ph
Ph
3ma
3na
3la
: 52% (E/Z = 1:10)
: 54% (E/Z = 1:5)
: 77% (E/Z = 1:12)
CN
O
O
O
3am
: 66% (E/Z = 1:6)
N
Q
N
Q
Ph
NHBoc
N
Q
O
Br
I
F
Ph
Ph
Ph
O
N
Q
3am
: CCDC 1910199
NH
3pa
3qa
: 59%
3oa
:
76%
: 77%
O
O
O
a
3an
: 70% (E/Z = 1:6)
N
Q
N
Q
N
Q
a Cu(OAc)2∙H2O (10 mol %). b Cu(OAc)2∙H2O (20 mol %).
MeS
O2N
NC
Ph
Ph
Ph
a
Scheme 3. Cupraelectro-catalyzed C–H alkynylation
cascade with alkyne 2.
3ra
3sa
3ta
: 55%
: 82% (E/Z = 1:2)
: 58% (E/Z = 1:3)
a Cu(OAc)2∙H2O (10 mol %).
Scheme 2. Cupraelectro-catalyzed C–H alkynylation for
isoindolones 3.
The user-friendly nature of the copper-catalyzed
electrochemical C−H activation was reflected by the gram-scale
synthesis of product 3aa, which proceeded with high catalytic
efficiency (Scheme 4).
Likewise, we explored the versatility of amenable acetylenes
2 (Scheme 3). A wide variety of alkynes 2 with electron-
donating and electron-withdrawing groups afforded the desired
isoindolinones 3ab-3aj. Generally, halo-substituents were well
accepted under the optimized reaction condition. Gratifyingly,
esters and cyanide groups-containing alkynes were chemo-
selectively tolerated by the cupraelectro-annulation manifold.
Notably, thiophene acetylene 2k was also found to be suitable,
efficiently furnishing the corresponding isoindolone 3ak. It is
noteworthy that the robustness of the copper-catalyzed C–H
activation further allowed for excellent efficacy with the alkyne
2n bearing an amino acid. The terminal alkynes with alkyl
substituent lead to the oxygenation products in low yield instead
of desired annulated products.
RVC
Pt
O
H
O
H
Q
Cu(OAc)2·H2O (5.0 mol %)
N
H
+
N
Q
NaOPiv
DMA, 11.5 h, 100 °C
CCE @ 50 mA
Ph
Ph
1a
2a
3aa
1.14 g
: 82% (E/Z = 1:5),
Scheme 4. Gram-scale cupraelectro-catalyzed isoindolone
synthesis.
Mechanistic Studies. In consideration of the unique
performance of the cupraelectro-catalyzed C–H activation, we
became intrigued by probing the catalyst’s mode of action. To
this end, intermolecular competition experiments between
different para-substituted benzamide 1 and alkyne 2 were
conducted (Scheme 5a). Thus, the electron-withdrawing
substrates 1l and 2g proved to be inherently superior,18 which
clearly highlights the complementary nature of our approach as
compared to functionalization of electron-rich anilides by
substrate SET-oxidation pathways.9b, 13 Reactions conducted in
the presence of isotopically-labeled CD3OD as the cosolvent
revealed the C–H cleavage not to be rate-determining (Scheme
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5b). Kinetic isotope effect (KIE) studies performed by in-
operando React-IR provided additional support for a facile C–
H scission (Scheme 5c). Head-space gas-chromatographic
analysis unraveled the formation of molecular hydrogen as the
Page 4 of 9
(Scheme 6), providing strong support for a C–H alkynylation
regime.
1
2
3
4
5
6
7
8
RVC
Pt
sole byproduct (Figure S5).
O
(a) competition experiments
Cu(OAc)2·H2O (5.0 mol %)
RVC
Pt
N
Q
O
H
O
O
H
NaOPiv
Cu(OAc)2·H2O (5.0 mol %)
Q
N
H
DMA, 6 h, 100 °C
CCE @ 6.0 mA
O
+
+
N
Q
N
Q
Ph
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
R
Me
Q
F3
C
Ph
N
Ph
Ph
H
3aa
: 81% (E/Z = 1:13)
R = Me: 1i
2a
3ia: 10%
3la: 32%
3la/3ia = 3.2
R = CF3
:
1l
9
O
Ph
RVC
Pt
without electricity
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11
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O
H
O
O
4
N
Q
Q
Cu(OAc)2·H2O (5.0 mol %)
N
H
NaOPiv
DMA, 6 h, 100 °C
+
+
N
Q
N
Q
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
Ph
R
Me
CF3
3aa
: 80% (E/Z = 1:5)
R = Me: 2b
R = CF3
2g
3ag/3ab = 2.3
1a
3ab: 12%
3ag: 27%
:
Scheme 6. Support for C–H alkynylation pathway.
(b) H/D exchange experiment
< 5% D
< 5% D
RVC
Pt
O
H/D
H/D
O
H
O
H
Q
N
Q
Cu(OAc)2·H2O (5.0 mol %)
NaOPiv
DMA/CD3OD (3.6 mL/0.4 mL)
6 h, 80 °C
Furthermore, we conducted detailed cyclic voltammetry
studies (Figure 2). In the presence of substrate 1a, the copper(II)
catalyst exhibited a pronounced oxidative current at 0.95 V
versus SCE, while Cu(OAc)2 itself did not reveal any relevant
competitive oxidation peak. These findings are suggestive of
the formation of a copper(II) complex 5, which is in turn
oxidized to a copper(III) intermediate. Subsequent C–H
activation and reductive elimination give rise to a CuOAc
species, which was shown to be easily reoxidized at 0.05 V
versus SCE to generate the initial copper(II) salt. In the presence
of substrate 1a, CuOAc exhibited oxidative currents at both
previously described potentials.
N
+
N
Q
+
H
H
H
Ph
Ph
H/D
CCE @ 6.0 mA
80% D
[D]n-3aa: 29% (E/Z = 1:12)
1a
(c) KIE studies
O
2a
[D]n-1a: 49%
RVC
Pt
O
H
Q
N
Cu(OAc)2·H2O (5.0 mol %)
+
H5/D5
H
N
Q
H4/D4
NaOPiv
DMA, 3 h, 100 °C
CCE @ 6.0 mA
Ph
Ph
kH/kD = 1.2
1a or [D]5-1a
2a
3aa or [D]4-3aa
(d) Reaction profile by in-operando React-IR
Scheme 5. Summary of key mechanistic findings.
Moreover, the independently prepared ortho-alkynylated
substrate 4 successfully delivered the desired product 3aa
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2
3
4
5
6
7
Decarboxylative C–H/C–C scission. Finally, the robustness
of our cupraelectro-catalyzed C–H activation was mirrored by
not being restricted to terminal alkynes 2. Indeed, easily
accessible alkynyl carboxylic acids 11 proved also applicable
under otherwise identical reaction conditions, effectively
providing the desired isoindolone
3
products by
decarboxylative19 C–H/C–C cleavage (Scheme 8).
8
9
RVC
Pt
O
OH
O
H
10
11
12
13
14
15
16
17
18
19
20
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60
O
Q
Cu(OAc)2·H2O (5.0 mol %)
N
H
+
N
Q
NaOPiv
DMA, 6 h, 100 °C
CCE @ 6.0 mA
R
R
1a
11
3
O
O
O
O
N
Q
N
Q
N
Q
N Q
Me
: 51% (E/Z = 1:7)
tBu
CF3
3ag
: 56% (E/Z = 1:2)
3aa
3ab
3ad
: 61% (E/Z = 1:10)
: 52% (E/Z = 1:20)
Scheme 8. Decarboxylative cupraelectro-catalyzed C–H/C–
C scission.
Figure 2. Cyclic voltammetry. General condition: DMA, 0.1 M
nBu4NPF6, 5 mM HOAc, 5 mM substrates, 100 mV/s.
CONCLUSIONS
In conclusion, we have reported on the first electrooxidative
cascade annulation by copper-catalyzed C–H alkynylation.
Based on our detailed mechanistic studies, we propose a
plausible catalytic cycle to commence by substrate coordination
and subsequent anodic copper(II) oxidation, thus forming the
catalytically competent copper(III) carboxylate species 6
(Scheme 7). Thereafter, facile carboxylate-assisted C–H
activation on the electron-deficient benzamide generates the
copper(III) intermediate 8. Then, metalation of the terminal
alkyne by carboxylate assistance, along with subsequent
reductive elimination delivers the C–H alkynylated arene 4,
which was shown to undergo cyclization towards the desired
isoindolone 3. Finally, the copper(I) complex is oxidized at the
anode by proton-coupled electron transfer to regenerate the
catalytically active copper(III) species.
Thus,
a versatile cupraelectro-catalyzed domino regime
featured excellent tolerance of synthetically useful functional
groups and broad substrate scope, including electron-deficient
benzamides. The cupraelectrocatalysis enabled sustainable C–
H functionalization in the absence of toxic metal oxidants and
generated molecular hydrogen as sole by-product. Detailed
mechanistic studies provided strong support for an
unprecedented C–H alkynylation by facile C–H activation, and
set the stage for novel C–H/C–C functionalization in terms of
decarboxylative metallaelectro-catalysis.
AUTHOR INFORMATION
O
Q
N
Corresponding Author
cathodic reduction
H
H
H
H2
*E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
2H
anodic oxidation
+
NaOPiv
O
CuII(OPiv)2
O
HOPiv
10
Author Contributions
Q
N
H
CuI(OPiv)
‡C.T. and U.D. contributed equally to this work.
9
N
II
Notes
Cu
N
reductive elimination
OPiv
4
The authors declare no competing financial interests.
HOPiv
O
5
N
NaOPiv
ASSOCIATED CONTENT
Supporting Information
III
Cu
N
anodic oxidation
H
O
O
8
N
Q
The Supporting Information is available free of charge on the
ACS Publications website.
N
III
Cu
OPiv
6
N
PivO
ligand exchange
HOPiv
3
O
Detailed experimental procedures, compound characterization data
(PDF)
Crystallographic data for C25H15N3O (CIF)
C–H activation
N
H
III
Cu
OPiv
7
N
2
ACKNOWLEDGMENT
Scheme 7. Proposed catalytic cycle.
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5619. (d) Waldvogel, S. R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C. J.
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award),
the CSC (Scholarship to C.T.) and the DAAD (fellowship to U.D.)
is gratefully acknowledged. We thank Dr. Christopher Golz
(Göttingen University) for the X-ray diffraction analysis.
Electrochemical Arylation Reaction. Chem. Rev. 2018, 118, 6706-
6765. (e) Tang, S.; Liu, Y.; Lei, A. Electrochemical Oxidative Cross-
coupling with Hydrogen Evolution: A Green and Sustainable Way for
Bond Formation. Chem 2018, 4, 27-45. (f) Sauermann, N.; Meyer, T.
H.; Qiu, Y.; Ackermann, L. Electrocatalytic C–H Activation. ACS
Catal. 2018, 8, 7086-7103. (g) Sauermann, N.; Meyer, T. H.;
Ackermann, L. Electrochemical Cobalt-Catalyzed C−H Activation.
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Products. Angew. Chem. Int. Ed. 2018, 57, 6018-6041. (i) Moeller, K.
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Electrochemical Reactions. Chem. Rev. 2018, 118, 4817-4833. (j)
Kärkäs, M. D. Electrochemical Strategies for C–H Functionalization
and C–N Bond Formation. Chem. Soc. Rev. 2018, 47, 5786-5865. (k)
Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic
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O
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CO2H
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CO
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Earth-abundant Cu
C–H Alkynylation
Electron-Deficient Arenes
Bioactive Isoindolones
Decarboxylative
C–H/C–C scission
Electricity as oxidant
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