Electrooxidative Rhodium-Catalyzed [5+2] Annulations via C?H/O?H Activations

Article abstract of DOI:10.1002/anie.202016895

Electrooxidative annulations involving mild transition metal-catalyzed C?H activation have emerged as a transformative strategy for the rapid construction of five- and six-membered heterocycles. In contrast, we herein describe the first electrochemical metal-catalyzed [5+2] cycloadditions to assemble valuable seven-membered benzoxepine skeletons by C?H/O?H activation. The efficient alkyne annulation featured ample substrate scope, using electricity as the only oxidant. Mechanistic studies provided strong support for a rhodium(III/I) regime, involving a benzoxepine-coordinated rhodium(I) sandwich complex as the catalyst resting state, which was re-oxidized to rhodium(III) by anodic oxidation.

Full text of DOI:10.1002/anie.202016895

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International Edition: doi.org/10.1002/anie.202016895
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Electrochemistry
Hot Paper
Electrooxidative Rhodium-Catalyzed [5+2] Annulations via
À
À
C H/O H Activations
Yulei Wang, Jo¼o C. A. Oliveira, Zhipeng Lin, and Lutz Ackermann*
Abstract: Electrooxidative annulations involving mild transi-
À
tion metal-catalyzed C H activation have emerged as a trans-
formative strategy for the rapid construction of five- and six-
membered heterocycles. In contrast, we herein describe the first
electrochemical metal-catalyzed [5+2] cycloadditions to
assemble valuable seven-membered benzoxepine skeletons by
À
À
C H/O H activation. The efficient alkyne annulation featured
ample substrate scope, using electricity as the only oxidant.
Mechanistic studies provided strong support for a rhodium(III/
I) regime, involving a benzoxepine-coordinated rhodium(I)
sandwich complex as the catalyst resting state, which was re-
oxidized to rhodium(III) by anodic oxidation.
À
B
ased on major achievements in the C H activation arena
during the past two decades, transition metal-catalyzed
annulations involving the activation of otherwise unreactive
À
C H bonds have revolutionized the art of preparing cyclic
compounds.[1–4] Despite indisputable advances, sacrificial
chemical oxidants, such as Cu(OAc)2 and AgOAc, are
generally required to facilitate these processes, thus resulting
in the generation of undesired byproducts and reducing the
atom economy.
À
Scheme 1. Electrochemical metal-catalyzed C H annulation.
Electricity has been considered as a green and atom-
economic redox equivalent.[5,6] Significant recent momentum
has been gained by the merger of electrocatalysis with
[7–11]
À
organometallic C H activation.
These reactions have
annulations has proven elusive. Moreover, while rhodium
À
provided efficient routes for the assembly of a variety of
heterocycles, normally five- and six-membered rings through
formal [3+2][9] or [4+1][10] or [4+2][11] cycloadditions, respec-
tively, with major contributions by the groups of Mei, Lei, Xu,
and Ackermann, among others (Scheme 1b). However, while
seven-membered rings, such as benzoxepine derivatives, are
the core structures of many natural products and pharmaco-
logically relevant molecules (Scheme 1a),[12] the construction
of these scaffolds by means of metallaelectro-catalyzed
catalysts have been widely used in C H activation, the key
low-valent rhodium(I) intermediates could seldom be iso-
lated and their redox-chemistry was rarely studied by electro-
À
analysis. Within our program on sustainable C H activa-
tion,[13] we herein report on a uniquely efficient electro-
oxidative rhodium(III/I)-catalyzed annulation reaction to
assemble the valuable seven-membered benzoxepine skele-
ton (Scheme 1b). Salient features of our approach comprise
a) the first electrooxidative [5+2] cycloaddition, b) annula-
À
À
tions by resource economical O H/C H functionalization,
c) electrons as catalysts in cathodic proton reduction, d) iso-
lation of key rhodium(I) intermediates and e) detailed
mechanistic insights into electrooxidative rhodium catalysis.
We initiated our studies by exploring reaction conditions
for the envisioned electrochemical [5+2] cycloadditions using
2-vinylphenol (1a) and diphenylacetylene (2a) in an undi-
vided cell setup equipped with graphite felt (GF) and
platinum plate (Pt) as anode and cathode material, respec-
tively (Table 1). After considerable experimentations, the
desired product 3aa was isolated in 88% yield with
[Cp*RhCl2]2 (2.5 mol%), NaOPiv (2.0 equiv) as additive in
tAmOH/H2O (3:1) at 1008C for 18 h (Table 1, entry 1). The
[5+2] annulation was not viable in the absence of NaOPiv,[14]
while KOAc in lieu of NaOPiv afforded a sharp decrease of
[*] Dr. Y. Wang, Dr. J. C. A. Oliveira, Z. Lin, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
and Wçhler Research Institute for Sustainable Chemistry
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016895.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used
for commercial purposes.
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Table 1: Optimization of the rhodium-catalyzed [5+2] cycloadditions.[a]
Entry
Variation from standard conditions
3aa [%][b]
1
2
3
4
5
6
7
8
no change
no NaOPiv
KOAc in place of NaOPiv
H2O
tAmOH
GF as cathode electrode
8 mA, 9 h
no electricity
88
trace
44
47
15
trace
65
7
9
under N2
79
0
0
10
11
12
Pd(OAc)2 in place of [Cp*RhCl2]2
[Cp*Col2]2 in place of [Cp*RhCl2]2
[Cp*IrCl2]2 in place of [Cp*RhCl2]2
0
[a] Undivided cell, GF anode, Pt cathode, constant current=4 mA, 1a
(1.0 mmol), 2a (0.5 mmol), NaOPiv (1.0 mmol), [Cp*RhCl2]2
(2.5 mol%), solvent (4 mL), under air, 18 h. [b] Yields of isolated product
3aa.
the yield (Table 1, entries 2–3). With H2O or tAmOH alone as
the solvent the electrocatalysis proved to be inefficient
(Table 1, entries 4–5). Replacing the platinum cathode by
a
GF electrode inhibited the electrocatalysis (Table 1,
entry 6). Increasing the current to 8 mA reduced the yield
of product 3aa to 65%, and a control experiment confirmed
the essential role of the electricity for the electrooxidative
annulation (Table 1, entries 7–9). Reactions with other tran-
sition-metal catalysts, including Pd(OAc)2 as well as Cp*-
ligated iridium and cobalt complexes, proved to be ineffective
for the annulation process (Table 1, entries 10–12).
With the optimized reaction conditions for the electro-
chemical [5+2] cycloadditions in hand (Table 1, entry 1), its
performance was first explored with a set of substituted
alkynes 2 (Scheme 2). The annulation was amenable to
diverse diaryl alkynes 2 featuring both electron-withdrawing
as well as electron-donating substituents on the aryl group
(3ab–3an). Functional groups, including chloro, bromo, and
even alkyl chloride as well as unprotected primary alcohol,
were well tolerated. The annulation with unsymmetrical
diaryl alkynes 2o and 2p results in 3.6:1 and 4.7:1 regiose-
lectivities, respectively. The rhodaelectro-catalysis was also
effective for dialkyl alkyne 2q. Notably, unsymmetrical
arylalkyl alkynes 2r–2w were also efficiently converted to
the corresponding benzoxepines with high levels of regiocon-
trol placing the alkyl group distal to the heteroatom (3ar–
3aw). This regioselectivity was assessed by means of compu-
tational studies at the PW6B95-D4/def2-QZVP + SMD
Scheme 2. Rhodaelectro-catalyzed [5+2] annulations with alkynes 2.
1 (Scheme 3). Various phenols 1 were thereby selectively
converted into the desired products 3 in high to excellent
yields (3ba–3ma). Remarkably, the power of the metal-
À
laelectrocatalysis was embodied in the chemo-selective C H
(methanol)//PBE0-D3(BJ)/def2-SVP
level
of
theory
functionalization/annulation with sensitive iodovinylphenol
1l to afford the desired product (3la).
(Figure 1).[15] The regioisomer 3aw was shown to be favored,
placing the aryl group proximal to the heteroatom. Non-
covalent secondary interactions play a dominant role in the
stabilization of the preferred transition state.
The fluorescent BODIPY motifs are widely used as
effective biological labels, luminescent tags and laser dyes.[17]
To our delight, the BODIPY-containing alkynes are suitable
substrates for the metallaelectro-catalyzed annulations, and
corresponding fluorescence-labeled benzoxepines (3ax–3ay)
The scope of the electrorhoda-catalyzed annulative reac-
tion was examined with diversely substituted 2-vinylphenols
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Scheme 3. Rhodaelectro-catalyzed [5+2] cycloadditions with 2-vinylphe-
nols. [a] 5.0 mol% [RhCp*Cl2]2.
Figure 1. Computed Gibbs free energy profiles in kcalmolÀ1 for the
regioselectivity of the migratory insertion step of alkyne 3w calculated
at the PW6B95-D4/def2-QZVP+SMD(methanol)//PBE0-D3(BJ)/def2-
SVP level of theory and visualization of noncovalent interactions
calculated from the NCI plot for the respective transition states. In the
latter, strong attractive interactions are given in blue and weak
attractive interactions are given in green, respectively, while red
corresponds to strong repulsive interactions.
could be easily obtained in one step (Scheme 4a). This
À
transition metal-catalyzed C H activation/annulation to
assemble various BODIPY-labeled heterocycles would have
great potential applications in drug deliveries, dyes, and
optoelectronics.
The scalability of the electrochemical rhodium-catalyzed
[5+2] annulation was further demonstrated for the assembly
of benzoxepines 3. The gram-scale reaction of substrates 1a
and 2a hence yielded 1.33 g of the desired product 3aa
(Scheme 4b).
Scheme 4. a) Syntheses of BODIPY-labeled benzoxepines. b) Gram-
scale synthesis of 3aa.
Cp*Rh(OPiv)2 (Scheme 5d). Increasing the electric current
resulted in a higher initial reaction rate, indicating the
reoxidation of rhodium(I) to rhodium(III) to be the rate-
determining step (RDS) (Scheme 6a). H/D exchange experi-
ments were conducted using D2O as the deuterium source,
and deuterium incorporation was not observed in the
recovered 2-vinylphenols 1a (Scheme 6b). Kinetic studies
To gain further insight into the reaction mechanism, we
conducted a series of experiments. Monitoring the catalytic
process by NMR spectroscopy revealed that a low-valent
rhodium complex 4 was likely the catalyst resting state in the
electrorhoda-catalyzed annulative reaction (Scheme 5a).
Notably, the corresponding rhodium(I) complexes 4aa and
4aj could be prepared and isolated by the reaction of
Cp*Rh(OAc)2 with the substrates 1a and 2a or 2j, respec-
tively. X-ray diffraction analysis featured rhodium(I) sand-
wich complexes in which the benzoxepines 3 are coordinated
to the metal center as four-electron ligands (Scheme 5b).[16]
Complex 4aa proved to be competent in the catalytic reaction
(Scheme 5c). Electrolysis of 4aa released product 3aa, and
the rhodium(I) was oxidized to the rhodium(III) species
À
suggested a facial vinylic C H metalation with a KIE value of
kH/kD ꢀ 1.0 (Scheme 6c). Competition experiments with
alkynes 2a and 2j revealed the greater reactivity of the
electron-deficient alkyne 2j (Scheme 6d).
CV studies of rhodium(I) complexes 4aa and 4aj
exhibited irreversible oxidation waves at À0.058 V versus
Fc0/+ and À0.029 V versus Fc0/+, respectively (Figure 2). It is
reasonable that the latter has a higher oxidation potential
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Scheme 6. Summary of key mechanistic findings.
Scheme 5. Isolation and electrolysis studies of rhodium(I) intermedi-
ates.
since 4aj possesses a electron-deficient metal center com-
pared to 4aa. A constant potential was conducted at 1.0 V
affording the desired product 3aa in 61% yield. Additional
CV studies showed that the rhodium(I) intermediates 4aa
and 4aj had lower oxidation potential than the substrates and
products (Figure S10). The addition of PivOH had no
significant influence on the oxidation potential of complex
4aa (Figure S11).
On the basis of our findings, a plausible catalytic cycle is
À
À
presented that commences with a facile O H/C H activation
to afford a rhodacycle A (Figure 3). Then, alkyne coordina-
tion–insertion occurs to produce intermediate C, which
rapidly undergoes reductive elimination to deliver the
rhodium(I) sandwich complex 4. Finally, the rhodium(I)
species is re-oxidized to rhodium(III) at the anode, releasing
the desired product 3 and generating molecular hydrogen as
the by-product at the cathode. An alternative oxidation-
Figure 2. Cyclic voltammetry studies. Conditions: 4aa (2.5 mm) or 4aj
(2.5 mm), nBu4NPF6 (0.1 m), MeCN, 100 mVsÀ1
.
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depicted in Figure S9.[15]
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À
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Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz
award to L.A.), the Alexander von Humboldt Foundation
(fellowship to Y.W.), and the CSC (fellowship to Z.L.) is
gratefully acknowledged. We thank Dr. Christopher Golz
(Gçttingen University) for assistance with the X-ray diffrac-
tion analysis. Open access funding enabled and organized by
Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
À
Keywords: [5+2] cycloaddition · benzoxepine · C H activation ·
electrochemistry · electrooxidative annulation
À
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[16] Deposition numbers 2042970 (3ak), 2042973 (3as), 2012969
(3ka), 2042968 (4aa) and 2042967 (4aj) contain the supplemen-
tary crystallographic data for this paper. These data are provided
free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access
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Manuscript received: December 20, 2020
Accepted manuscript online: January 20, 2021
Version of record online: February 8, 2021
6424 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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