Electrooxidative Iridium-Catalyzed Regioselective Annulation of Benzoic Acids with Internal Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c04168

Electrochemically driven, Cp*Ir(III)-catalyzed regioselective annulative couplings of benzoic acids with alkynes have been established herein. The combination of iridium catalyst and electricity not only circumvents the need for stoichiometric amount of chemical oxidant, but also ensures broad reaction compatibility with a wide array of sterically and electronically diverse substrates. This electrochemical approach represents a sustainable strategy as an ideal alternative and supplement to the oxidative annulations methodology to be engaged in the synthesis of isocoumarin derivatives.

Full text of DOI:10.1021/acs.orglett.0c04168

pubs.acs.org/OrgLett
Letter
Electrooxidative Iridium-Catalyzed Regioselective Annulation of
Benzoic Acids with Internal Alkynes
Qi-Liang Yang,# Hong-Wei Jia,# Ying Liu, Yi-Kang Xing, Rui-Cong Ma, Man-Man Wang, Gui-Rong Qu,
Tian-Sheng Mei,* and Hai-Ming Guo*
Cite This: Org. Lett. 2021, 23, 1209−1215
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ABSTRACT: Electrochemically driven, Cp*Ir(III)-catalyzed re-
gioselective annulative couplings of benzoic acids with alkynes have
been established herein. The combination of iridium catalyst and
electricity not only circumvents the need for stoichiometric amount
of chemical oxidant, but also ensures broad reaction compatibility
with a wide array of sterically and electronically diverse substrates.
This electrochemical approach represents a sustainable strategy as
an ideal alternative and supplement to the oxidative annulations
methodology to be engaged in the synthesis of isocoumarin
derivatives.
socoumarins are not only important synthetic intermediates
in complex heterocycle constructions, but also an integral
Scheme 1. Electrooxidative Ir-Catalyzed Regioselective
Annulation
I
and common part of many natural products and bioactive
molecules.1 Transition-metal-catalyzed oxidative annulations of
benzoic acids with alkynes to construct the isocoumarin
skeleton have been recognized as one of the most efficient
synthetic approaches with the highest step- and atom-
economy.2 Consequently, a series of classic transition metals
including cobalt-,3 ruthenium-,4 rhodium-,5 and iridium-
catalyzed5a,6 oxidative annulation have been well-developed.
Despite indisputable advances, these coupling reactions usually
require stoichiometric amounts of an external organic- or
metal-based oxidant or an internal oxidizing group for catalyst
turnover.7 The initial investigating chemical oxidants and the
disposal of wastes at the end of the reaction remain challenges
for these reactions, which compromise the synthetic utility and
environmental merits of these approaches (Scheme 1a).
The merging of electrochemistry and transition-metal
catalysis has been demonstrated as an attractive, powerful,
and environmentally friendly strategy toward sustainable
synthesis, featuring electricity as a waste-free and renewable
oxidant or reductant.8 In this context, many elegant examples
of electrochemically driven, metal-catalyzed sustainable C−H
bond functionalization reactions have been developed.9
Nevertheless, to our knowledge, only a single example of
electrochemical oxidative cyclization of internal alkynes with
benzoic acids has been reported by the Ackermann group in
2018, employing ruthenaelectrocatalysis.10
inert C−H functionalization reactions,14 featuring unique
reactivities, great selectivities, and rich reaction types that
Received: December 16, 2020
Published: February 4, 2021
Whereas electrochemical C−H activation catalyzed by
Rh(III)11 and Ru(II)12 catalysts has been reasonably well-
investigated, surprisingly little attention has been given to
Cp*Ir(III) catalysts.13 Meanwhile, Cp*Ir(III) complexes have
been identified as powerful catalysts that have enabled various
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 1209−1215
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could be well applied to late-stage modifications of bioactive
molecules. Cp*Ir(III) catalysts should have great synthetic
potential in C−H functionalization with electrochemistry.
Given our continuous interest in site-selective C−H
functionalization induced by metalla-electrocatalysis,15 we
report herein an unprecedented iridium-catalyzed electro-
oxidative annulation of easily accessible (hetero)aromatic acids
with a wide array of internal alkynes through weak ortho-
coordinating strategy (Scheme 1b).
this methodology. Initially, we explored the reactivity of
different alkynes 2 (Scheme 2). Highly coordinating dialkyl
Scheme 2. Ir-Catalyzed Electrochemical Annulation of
a−c
Benzoic Acid 1a with Alkynes 2
We commenced our studies by using the 2-methylbenzoic
acid 1a and diphenylacetylene 2a as the model substrates. By
using 3 mol % (Cp*IrCl2)2 as the catalyst and 3.0 equiv of
nBu4NOAc as the electrolyte, the annulation product 3a could
be obtained in 90% isolated yield under 1.5 mA constant
current in an undivided cell with two Pt plate electrodes at 60
°C. Methanol was identified as the optimal solvent. The
combination of other solvents (EtOH, CF3CH2OH, and
n
HFIP) with Bu4NOAc result in much lower yields (Table 1,
a
Table 1. Condition Optimization
b
entry
variation from standard conditions above
yields (%)
c
1
2
3
4
5
6
none
99 (90)
EtOH, CF3CH2OH, HFIP instead of MeOH
3 mA (6 h), 6 mA (3 h) instead of 1.5 mA (12 h)
30 °C, 40 °C instead of 60 °C
76, <5, <5
68, 67
57, 67
n
NaOAc, KOPiv, K2CO3 instead of Bu4NOAc
96, 95, <5
<5
nBu4NBF4, Bu4NPF6, Bu4NClO4 instead of
n
n
nBu4NOAc
7
RVC, graphite felt, graphite rod anode instead of Pt 94, 95, 28
anode
c
8
9
10
decagram scale
no (Cp*IrCl2)2
no electric current
72 (7.44 g)
nr
<5
a
Reaction conditions: substrate 1a (0.24 mmol, 1.2 equiv), alkyne 2
(0.2 mmol, 1.0 equiv), nBu4NOAc (0.60 mmol, 3.0 equiv),
(Cp*IrCl2)2 (3.0 mol %), MeOH (3.0 mL), 60 °C (oil bath
d
b
a
temperature), 1.5 mA, and 12 h (3.4 F/mol). Isolated yields.
Reaction conditions: two platinum plate electrodes (each 15 × 10
mm2), substrate 1a (0.24 mmol, 1.2 equiv), alkyne 2a (0.20 mmol, 1.0
equiv), nBu4NOAc (0.60 mmol, 3.0 equiv), (Cp*IrCl2)2 (3.0 mol %),
MeOH (3.0 mL), 60 °C (oil bath temperature), 1.5 mA, and 12 h
c
d
Regioselectivity ratio in parentheses. 5.0 mmol scale.
acetylenes such as hex-3-yne, oct-4-yne, and dec-5-yne gave
products 3b−3d in excellent yields. When more sterically
hindered arylalkynes were used instead of alkylalkynes, yields
significantly decreased (3e−3k). Notably, asymmetrically
substituted alkynes delivered the desired product in 6:1−
15:1 regioselectivities (3l−3x). Moreover, the protocol
developed here could also find applications in the diversifica-
tion of pharmacologically active molecules (3y), showcasing
the potential utility of this chemistry.
The scope of benzoic acids was further examined under
optimized conditions (Scheme 3). This robust iridium
electrocatalysis displayed a remarkable tolerance to many
sensitive, important, and valuable functional groups in the
aromatic ring of benzoic acids, including alkyl, ether, fluoro,
chloro, bromo, iodo, trifluoromethyl, nitro, hydroxyl, and ester
substituents, setting the stage for subsequent late-stage
diversifications. Generally, monosubstituted benzoic acids
with electron-donating and electron-neutral substituents, such
as methoxy, methyl, and halogen, readily reacted in satisfactory
yields (4e−4o). Strong electron-withdrawing groups (CO2Me,
CF3, and NO2) afforded relatively lower yields due to lower
conversion (4p−4r). As for substrates possessing a meta
b
(3.4 F/mol). 1H NMR yields using CH2Br2 as an internal standard.
c
d
Isolated yields. nr: no reaction.
entry 2). Keeping constant the electric quantity and raising the
operating current to 3 or 6 mA would led to the reduced yields
(Table 1, entry 3). Lowering the reaction temperature also
resulted in deceased conversions (Table 1, entry 4).
Carboxylate additives proved critical for the transformation.
Switching Bu4NOAc to NaOAc or KOPiv provided similar
results (Table 1, entry 5). In contrast, alternative electrolytes
including Bu4NBF4, Bu4NPF6, and Bu4NClO4 were entirely
ineffective (Table 1, entry 6). Screening of electrods showed
that both reticulated vitreous carbon and graphite felt could
effectively substitute for platinum plate as the anode, but not
graphite rod (Table 1, entry 7). This reaction could be readily
scaled up to decagram scale, albeit in lower yield (Table 1,
entry 8). Control experiments showed that both iridium
catalyst (Table 1, entry 9) and electric current (Table 1, entry
10) were indispensable to the reaction.
n
n
n
n
With the optimized iridium-catalyzed electrooxidative C−H
activation in hand, we sought to investigate the generality of
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Letter
Scheme 3. Ir-Catalyzed Electrochemical Annulation of
Benzoic Acid 1 with Alkynes 2c
Scheme 4. Ir-Catalyzed Electrochemical Annulation of
a b
a b
,
,
Benzoic Acid 1 with tert-Propargyl Alcohols 5
a
Reaction conditions: substrate 1 (0.24 mmol, 1.2 equiv), alkyne 2c
(0.2 mmol, 1.0 equiv), nBu4NOAc (0.60 mmol, 3.0 equiv),
(Cp*IrCl2)2 (3.0 mol %), MeOH (3.0 mL), 60 °C (oil bath
b
temperature), 1.5 mA, and 12 h (3.4 F/mol). Isolated yields.
a
Reaction conditions: substrate 1 (0.24 mmol, 1.2 equiv), alkyne 5
(0.20 mmol, 1.0 equiv), nBu4NOAc (0.60 mmol, 3.0 equiv),
(Cp*IrCl2)2 (3.0 mol %), MeOH (3.0 mL), 60 °C (oil bath
temperature), 1.5 mA, and 12 h (3.4 F/mol). Isolated yields. 6.0
mmol scale.
methyl group, annulation preferentially occurred at the less
sterically congested C−H bond (4b). Moreover, heterocyclic
carboxylic acids and indole-, furan-, and thiophenecarboxylic
acids also efficiently participated in this transformation, leading
to isocoumarins 4u−4w in 70, 73, and 33% yields, respectively.
To better define the generality of this methodology, we next
extended the electrooxidative coupling reaction system to tert-
propargyl alcohols 5. To our delight, synthetically meaningful
tert-propargyl alcohols 5 were smoothly converted into the
corresponding isocoumarins 6 with excellent levels of
regioselectivity under otherwise identical reaction conditions
(Scheme 4). The tertiary hydroxyl group of propargylic alcohol
plays a significant role for the observed reverse regioselectivity,
probably due to its steric hindrance and binding affinity with
the iridium catalyst.16
b
c
Scheme 5. Ir-Catalyzed Electrochemical Annulation of
a−c
Benzoic Acid 1 with Trifluoromethylated Alkyne 7
Gratifyingly, this electrooxidative coupling reaction could be
further extended to the trifluoromethylated alkyne 7 shown in
Scheme 5 using modified, basic conditions (see Table S6 in the
Supporting Information). Using (Cp*IrCl2)2 as the catalyst (5
mol %) and CF3CH2OH as the solvent at 50 °C, the
corresponding trifluoromethylated isocoumarins 8a−8c were
obtained in good yields with high levels of regioselectivity,
generally placing the trifluoromethyl group in all cases
proximal to the oxygen heteroatom. In sharp contrast, Ru-
catalyzed annulation under anodic oxidative conditions
afforded 8b in <5% yield (see the Supporting Information).
It is important to note that this versatile iridium-catalyzed
electrochemical alkyne annulation could serve as an alternative
and complementary approach to the recently reported
method.6,10
a
Reaction conditions: substrate 1 (0.20 mmol, 1.0 equiv), alkyne 7
(0.40 mmol, 2.0 equiv), nBu4NOAc (0.60 mmol, 3.0 equiv),
(Cp*IrCl2)2 (5 mol %), CF3CH2OH (3.0 mL), 50 °C (oil bath
b
temperature), 1.5 mA, and 10 h (2.8 F/mol). Isolated yields.
c
Regioselectivity ratio in parentheses.
underwent smooth intramolecular cyclization when treated
with BF3·Et2O to deliver indeno[2,1-c]isocoumarin 9 in 89%
yield.6b Furthermore, treatment of 9 with Lawesson’s
reagent,17 (NH4)2CO3,18 and NaBH419 gave the corresponding
thioisocoumarins 10, 1(2H)-isoquinolone 11, and chromene
12 in 85%, 80%, and 70% yields, respectively (see the
Supporting Information, Scheme S1).
The synthetic utility of this reaction was substantiated by an
easily performed gram-scale reaction as demonstrated with the
synthesis of 3c and 6l. The isocoumarin derivative 6a
Several experiments have been performed to identify the
reaction mechanism. To compare the activity of alkynes, the
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treatment of benzoic acid 1a with diphenylacetylene 2a and
oct-4-yne 2c was tested, affording 3a and 3c in a 1:2.5 ratio as
determined from H NMR analysis, indicating that the alkyl-
substituted derivatives were converted preferentially (Scheme
6a). When an equimolar mixture of 1f and 1r was allowed to
competition experiment. In addition, a KIE value of ∼1.6 was
observed from a parallel single-component experiment using
1b and [D5]-1b (Scheme 6c). These results suggested that the
cleavage of C−H was probably involved in the rate-limiting
step. Subsequently, stoichiometric reactions were carried out.
The metalacycle intermediate 14 was isolated with good yield
in the reaction of 1a with IrCp*(OAc)2(DMSO).20 Then the
cyclometalated complex 14 was treated with 2a in the absence
of electricity, which gave the sandwich complex 15 with
isocoumarin 3a as the neutral ligand. This observation is a
strong testament to the facile reductive elimination of the
seven-membered iridacycle intermediate (Scheme 6d). Nota-
bly, both complexes 14 and 15 proved to be catalytically
competent species in the electrooxidative annulation. (Scheme
6e). Thereafter, the key reoxidation of the iridium(I) sandwich
complex 15 was probed by anodic oxidation in stoichiometric
experiments. When Ir(I) complex 15 was subjected to
electrolysis, 3a was obtained in 96% yield (Scheme 6f). This
result provided compelling evidence for the efficient anodic
oxidation of the iridium(I) intermediate by electrochemical
approach.
1
Scheme 6. Experimental Mechanistic Studies
Finally, we carried out cyclic voltammetry studies (Figure 1).
The oxidation potentials of 2-methylbenzoic acid 1a,
Figure 1. Cyclic voltammograms recorded in MeCN with 0.1 M
nBu4NPF6 as the supporting electrolyte: scan rate, 100 mV s−1,
substrate (4 mM), Pt electrode (area = 0.03 cm2) as the working
electrode, SCE as the reference electrode.
diphenylacetylene 2a, and isocoumarin 3a were found at
2.69, 1.88, and 1.74 V versus SCE, respectively, while iridacycle
15 showed a significantly lower oxidation potential at 0.79 V
versus SCE (curve e, Figure 1), indicating an initial anodic
iridium(I/III) oxidation with a concomitant release of 3a. In
light of preliminary experimental investigations and precedent
literatures,6,16 a possible catalytic cycle is proposed (see
Supporting Information, Scheme S3).
In conclusion, we have developed an electricity-powered,
Cp*Ir(III) catalyst enabled regioselective annulative coupling
of benzoic acids with internal alkynes. This technology
circumvents the need for external chemical oxidants and
ensures broad reaction compatibility with a wide range of
sterically and electronically diverse substrates, allowing facile
access to diversely functionalized isocoumarins in a highly
regioselective manner. Preliminary mechanistic studies provide
support for the facile organometallic C−H bond activation and
the effective anodic oxidation of the iridium(I) intermediate.
Further investigations aimed at developing more electro-
oxidative Ir-catalyzed C−H activations are ongoing in our
laboratory.
competitively couple with 2c, products 4e and 4q were
obtained in a 4:1 ratio, indicating that the electron-rich benzoic
acid was more reactive than its electron-deficient counterpart.
Next, an H/D exchange experiment was performed. Unlike
previously reported anodic Ru catalysis,10 almost no loss of
deuterium from [D5]-1b was observed, which indicates the
good stability of the C−Ir bond (Scheme 6b). A large kinetic
isotope effect (kH/kD = 3.0) was obtained in an intermolecular
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Letter
Rui-Cong Ma − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04168.
General information, experimental details, X-ray data,
and NMR spectral data (PDF)
Man-Man Wang − Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Key Laboratory
of Green Chemical Media and Reactions, Ministry of
Education, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, School
of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China
Gui-Rong Qu − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Accession Codes
CCDC 1878736, 1920134, 2014257, 2014259, 2014285,
2036876, 2043553, and 2052477 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Tian-Sheng Mei − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-4985-
1071; Email: mei7900@sioc.ac.cn
Hai-Ming Guo − Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Key Laboratory
of Green Chemical Media and Reactions, Ministry of
Education, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, School
of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0003-0629-4524; Email: ghm@htu.edu.cn
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04168
Author Contributions
#Q.-L.Y. and H.-W.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 22007028, 22071046, and
21821002), the National Government Guides Local Special
Funds for the Development of Science and Technology (No.
YDZX20204100001786), the Strategic Priority Research
Program of the Chinese Academy of Sciences (No.
XDB20000000), the Postdoctoral Program for Innovative
Talents (BX20190108), the China Postdoctoral Science
Foundation (2020M672242), and the 111 Project (No.
D17007).
Authors
Qi-Liang Yang − Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Key Laboratory
of Green Chemical Media and Reactions, Ministry of
Education, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, School
of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0003-4734-5391
Hong-Wei Jia − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Ying Liu − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Yi-Kang Xing − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
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