Photoredox Oxo-C(sp3)-H Bond Functionalization via in Situ Cu(I)-Acetylide Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b04277

A unified strategy for the synthesis of 2-vinyl heterocycles is reported. With visible light irradiation, simple and cheap CuCl is able to functionalize a terminal alkyne, giving Cu(I)-acetylide in situ. Unlike the case of noble metals or organic dye photocatalysts, this critical Cu(I)-acetylide not only activates the C-H bond of terminal alkynes but also serves as a photocatalyst to achieve varieties of 2-vinyl heterocycles in good to excellent yields, even for large scale and late-stage functionalization of natural product.

Full text of DOI:10.1021/acs.orglett.9b04277

pubs.acs.org/OrgLett
Letter
Photoredox Oxo-C(sp3)−H Bond Functionalization via in Situ Cu(I)-
Acetylide Catalysis
Zi-Qi Song, Zan Liu, Qi-Chao Gan, Tao Lei, Chen-Ho Tung, and Li-Zhu Wu*
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ABSTRACT: A unified strategy for the synthesis of 2-vinyl heterocycles is reported.
With visible light irradiation, simple and cheap CuCl is able to functionalize a terminal
alkyne, giving Cu(I)-acetylide in situ. Unlike the case of noble metals or organic dye
photocatalysts, this critical Cu(I)-acetylide not only activates the C−H bond of
terminal alkynes but also serves as a photocatalyst to achieve varieties of 2-vinyl heterocycles in good to excellent yields, even for
large scale and late-stage functionalization of natural product.
catalyst, oxo-C−H bond activation for the synthesis of a 2-
vinyl heterocycle has been established.
2-Vinyl heterocycle derivatives are core moieties spread across
a multitude of bioactive natural products as well as
pharmaceuticals.1 To achieve this important framework, direct
addition of heterocycle radicals to alkynes is particularly
attractive because it avoids prefunctionalization of substrates
and formation of vast amounts of byproducts.2 However, the
relatively high bond dissociation energy (BDE = 92.0 kcal/
mol),3a low polarity of oxo-C(sp3)−H bond, and high
Herein, we develop a photocatalyzed strategy for synthesis of
2-vinyl heterocycles with both oxo-C(sp3)−H and C(sp)−H
activation in the same reaction system. Taking advantage of
CuCl to activate the alkyne, the in situ generated Cu(I)-
acetylide complex10,12 exhibits visible light absorption.11,12
Strikingly, the excited Cu(I)-acetylide, with a long lifetime and
high reductive potential (E1/2 = −1.77 V vs SCE),11 is able to
deliver an electron11c to tert-butyl hydroperoxide (TBHP) for
reductive potential (E1/2 = +1.75 V vs SCE for THF)3b
red
make the direct activation of the α-C(sp3)−H bond of THF a
challenge.4 As a result, THF is widely used as a solvent for
both academic studies and industrial processes. On the other
hand, alkynes, unlike alkenes and enones,5 are not so active to
react with ether radicals, and the generated vinyl radical
intermediate would take part in other pathways instead of C−
C bond formation.6 Recent advances in visible-light photo-
redox catalysis have provided a mild way to activate oxo-C−H
bonds of ethers, followed by addition to alkynes (Scheme
t
the generation of the BuO• radical, which activates the α-
C(sp3)−H bond of the heterocycle for the subsequent
addition7a,14 to afford the desired products. Indeed, terminal
alkynes can rapidly be activated by CuCl under visible light
irradiation.10 In comparison with a noble-metal complex (such
as Ir and Ru) as a photoredox catalyst, inexpensive Cu(I) salt
and a readily available alkyne in situ give Cu(I)-acetylide as a
photocatalyst, greatly simplifying the reaction.13
Our initial study focused on the direct coupling of
phenylacetylene (1a) with THF (2a) as the model substrates.
When catalyzed by the simple copper(I) chloride salt using
TBHP as an HAT reagent precursor at room temperature, the
desired product 2-vinyltetrahydrofuran was obtained in 51%
yield with an E/Z ratio of 0.7 (Table 1, entry 1). Other
copper(I) halides (halide = bromide, iodide) give slightly
lower (Table 1, entries 2−3) yields of 50% and 44%,
respectively. Various HAT reagent precursors were tested,
identifying TBHP as the best (Table 1, entries 4−6). A
different performance was shown when the reaction was
performed with a series of bases, such as KOAc, Et3N, and
pyridine, revealing 2-methylpyridine to be the most effective
for the formation of the coupling product (3a) in 87% yield
7b
1).7−9 By combining eosin Y7a or [Ru(bpy)3]Cl2 as a
photocatalyst and the TBHP/NiCl2 complex8 as an oxidant/
Scheme 1. Photoredox Approaches to 2-Vinyl Heterocycles
Received: November 28, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04277
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
b
entry
CuX
oxidant
TBHP
TBHP
TBHP
DCP
DTBP
(NH4)2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
base
yield (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
CuI
−
−
−
−
−
−
KOAc
Et3N
51
50
44
<20
<20
0
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
−
32
53
f
pyridine
2-methylpyridine
58
f
10
87
c
11
−
−
−
0
0
0
d
12
e
13
CuCl
a
Reaction conditions: 1a (0.2 mmol), 2a (2.5 mL), MeCN (0.05
mL), CuX (1 mol %), oxidant (1 equiv), base (1 equiv), blue LEDs,
b
c
d
e
argon atmosphere, rt, 24 h. Isolated yield. No light. No CuCl. In
f
the air. Yield detected by GC-FID, using mesitylene as an internal
standard.
(Table 1, entry 10). Control experiments demonstrated that
the conversion of 3a was completely inhibited when CuCl was
absent from the reaction system, and no generation of 3a was
detected without visible light irradiation (Table 1, entries 11−
12). As a result, the visible-light-catalyzed Cu(I) mediated
vinylation reaction of THF was able to smoothly proceed
under optimized conditions, i.e., CuCl (1 mol %) with TBHP
and 2-methylpyridine in 0.05 mL of MeCN, irradiated by blue
LEDs at room temperature in an argon atmosphere (Table 1,
entry 10).
With the optimized conditions in hand, various aromatic
terminal alkynes were examined to explore the scope of
photoredox-catalyzed in situ Cu(I) mediated vinylation
reaction of heterocycles. As illustrated in Scheme 2, when
subjected to the optimal reaction conditions described above, a
series of the corresponding vinyl tetrahydrofuran product 3
were afforded smoothly in moderate to good isolated yields,
with E/Z isomeric ratios ranging from 0.1 to 4.1. By using
THF as both solvent and reactant, unsubstituted phenyl-
acetylene reacted with THF to give 2-styryltetrahydrofuran 3a
in a yield of 83% under the optimal reaction conditions.
Halogen-containing phenylacetylene showed similar activities
to those of phenylacetylene, as ortho-, meta-, and para-
halogenophenylacetylene affording corresponding addition
products 3b−3j in good yields. The introduction of an
electron-withdrawing group such as ester (3k−3m) had only a
slight effect on the reaction efficiency, resulting in moderate
yields. Phenylacetylenes bearing electron-donating groups
including methyl and methoxyl were also good reactants, and
the target products 3n−3u were obtained in moderate yields.
However, tert-butyl-substituted phenylacetylene (3q) gave the
desired product in a low yield of 44%, probably because of the
steric hindrance. Therefore, general reactivity could be reached
since both electron-withdrawing/-donating properties and the
substitution patterns (ortho, meta, para) on the aryl rings
seemed to exhibit little influence on the reaction efficiency.
Other aromatic heterocyclic terminal alkynes such as 2-
ethynylnaphthalene (3v) and 2-ethynylpyridine (3w) could
a
Reaction conditions: 1 (0.2 mmol), 2 (2.5 mL), MeCN (0.05 mL),
CuCl (1 mol %), TBHP (1 equiv), 2-methylpyridine (1 equiv), blue
LEDs, argon atmosphere, rt, 24 h. Isolated yield was based on 1.
also tolerate the reaction condition smoothly, giving the
corresponding products in moderate yields. Besides THF,
oxygen-containing heterocycles including dioxane (3x),
dioxolane (3y), and tetrahydropyran (3z) were suitable for
this transformation under the optimal conditions. Thus, this
visible light photocatalytic C−H functionalization method
clearly tolerates a broad spectrum of terminal alkyne partners.
To highlight the synthetic application, we developed the
functionalization of a natural product derivative. Estrone
derivative (1aa) was smoothly transferred into functionalized
estrone (3aa) with an E/Z isomeric ratio of 0.6 under the
standard reaction conditions. When the substrate loading was
scaled up, a yield of 72% was obtained after reaction under
optimal conditions, as shown in Scheme 3-1.
Since Cu(I)-phenylacetylide is an important intermediate
involved in the reaction process,12 we directly investigated
Cu(I)-phenylacetylide by UV−vis absorption (Figure 1-Left)
and luminescence (Figure 1-Right) analysis. CuCl and
phenylacetylene in degassed MeCN with irradiation by blue
LED soon gave Cu(I)-phenylacetylide as a yellow solid (Figure
1-Left).12c This in situ generated Cu(I) complex showed an
absorption peak at 460 nm,12c along with two emission peaks
B
https://dx.doi.org/10.1021/acs.orglett.9b04277
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Letter
Based on the above mechanistic results and previous
investigation, a plausible reaction mechanism was proposed
and illustrated in Scheme 4. The simple Cu(I) ion activates the
Scheme 3. Scale-up Reaction, Radical Capture and Kinetic
Isotope Effect Experiments
Scheme 4. A Plausible Mechanism
C−H bond of a terminal alkyne to produce the key
intermediate Cu(I)-phenylacetylide complex.10 Visible-light
irradiation of this in situ generated Cu(I)-phenylacetylide A
affords an excited state of Cu(I)-phenylacetylide A*,11 which
then undergoes an SET process to deliver an electron to TBHP
and generate the intermediate Cu(II)-phenylacetylide B11c and
a tert-butoxy radical (tBuO•). The tBuO• radical then abstracts
a hydrogen atom from THF to afford an α-oxo-carbon-
centered radical.7 Activated by the copper ion, the CC bond
of Cu(II)-phenylacetylide intermediate B tends to be attacked
by an ether radical,14 to generate carbon-centered intermediate
C. The intermediate C accepts the H• radical from THF to
furnish D. The ligand exchange process between D and the
terminal alkyne might give the intermediate A and desired
product 3a. The radical chain reaction mechanism might not
be excluded since the generated THF radical attacked
phenylacetylene directly to give the desired product.7
In conclusion, we have introduced in situ Cu(I)-catalysis for
the photoredox synthesis of 2-vinyl heterocycle derivatives. A
terminal alkyne is activated by CuCl to form a Cu(I)-acetylide
complex. Under visible-light irradiation at room temperature,
this in situ generated Cu(I)-acetylide complex as a photo-
catalyst reacts with an HAT precursor to activate the α-
C(sp3)−H bond of a heterocycle. Besides electron-deficient
alkynes, direct addition of the generated ether radical to
electron-rich/-neutral alkynes has successfully achieved the
coupling reaction. The natural product derivative and scale-up
reaction perform well under the conditions. With this protocol
using readily available starting materials and inexpensive
copper salts to form photocatalyst in situ, it is anticipated
that this approach would provide a useful design for a variety
of carbon/heteroatom-centered radicals addition to alkynes in
an economic and environmentally benign way.
Figure 1. (Left) UV−vis absorption spectra of 7.84 × 10−4 M Cu(I)-
phenylacetylide in degassed MeCN: preparation of Cu(I)-phenyl-
acetylide, CuCl (2 mg), and phenylacetylene (1 equiv) in degassed
MeCN before blue LED irradiation in the left tube and after blue
LED irradiation in the right tube. (Right) Luminescence spectra of
7.84 × 10−4 M Cu(I)-phenylacetylide (labeled by black line); with the
addition of 7.84 × 10−2 M TBHP (labeled by red line) in degassed
MeCN with excitation at 460 nm.
at 510 and 574 nm (Figure 1), which was in accordance with
other reported values.12c Meanwhile, simple CuCl and
phenylacetylene did not show the light absorbing property in
this test, respectively. Then, the ratio of Cu(I)-phenylacetylide
and TBHP was controlled to be the same as the reaction
system. As shown in Figure 1-Right, labeled by the red line, the
emission of the Cu(I) complex decreased as TBHP was
introduced into the solution, suggesting the single-electron
transfer (SET) process from Cu(I)-phenylacetylide to TBHP
quenched the emission of Cu(I)-phenylacetylide. When one or
more equivalent(s) of 2,2,6,6-tetramethylpiperidin-1-yloxy
(TEMPO) or 2,6-ditert-butyl-4-methylphenol (BHT) were
added into the reaction system, the reaction had varying
degrees of inhibition, as shown in Scheme 3-2. This
observation suggested that a radical intermediate might be
involved in the reaction pathway. We also investigated the
kinetic isotopic effect (KIE) by competition experiments as
illustrated in Scheme 3-3. The intermolecular kH/kD was
determined to be 3.5 based on 1H NMR spectroscopic analysis
of the isolated products. This isotopic effect implied that α-C−
H bond cleavage was probably involved in the rate-
determining step of this reaction. We further performed the
on−off light experiment (see Supporting Information) under
the optimal conditions. It demonstrated the transformation
process was not totally forbidden during the dark condition,
indicating that the radical chain reaction mechanism might be
involved in this reaction.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04277.
Materials and methods; characterization data for all
1
compounds, H and 13C NMR spectra (PDF)
C
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
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Li-Zhu Wu − Technical Institute of Physics and Chemistry,
The Chinese Academy of Sciences, Beijing, P. R. China,
and School of Future Technology, University of Chinese
Academy of Sciences, Beijing, P. R. China; orcid.org/
0000-0002-5561-9922; Email: lzwu@mail.ipc.ac.cn
Other Authors
Zi-Qi Song − Technical Institute of Physics and
Chemistry, The Chinese Academy of Sciences, Beijing, P. R.
China, and School of Future Technology, University of
Chinese Academy of Sciences, Beijing, P. R. China
Zan Liu − Technical Institute of Physics and Chemistry,
The Chinese Academy of Sciences, Beijing, P. R. China,
and School of Future Technology, University of Chinese
Academy of Sciences, Beijing, P. R. China
Qi-Chao Gan − Technical Institute of Physics and
Chemistry, The Chinese Academy of Sciences, Beijing, P. R.
China, and School of Future Technology, University of
Chinese Academy of Sciences, Beijing, P. R. China
Tao Lei − Technical Institute of Physics and Chemistry,
The Chinese Academy of Sciences, Beijing, P. R. China,
and School of Future Technology, University of Chinese
Academy of Sciences, Beijing, P. R. China
Chen-Ho Tung − Technical Institute of Physics and
Chemistry, The Chinese Academy of Sciences, Beijing, P. R.
China, and School of Future Technology, University of
Chinese Academy of Sciences, Beijing, P. R. China;
orcid.org/0000-0001-9999-9755
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addition to alkynes and related triple bond systems. Chem. Rev. 2013,
113, 813.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04277
́
(6) (a) Gomez-Balderas, R.; Coote, M. L.; Henry, D. J.; Fischer, H.;
Radom, L. What is the origin of the contrathermodynamic behavior in
methyl radical addition to alkynes versus alkenes? J. Phys. Chem. A
2003, 107, 6082. (b) Giese, B.; Lachhein, S. Addition of alkyl radicals
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Notes
The authors declare no competing financial interest.
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vinylation of tetrahydrofuran with alkynes through direct C−H bond
functionalization. Org. Lett. 2015, 17, 2522. (b) Feng, S.; Xie, X.;
Zhang, W.; Liu, L.; Zhong, Z.; Xu, D.; She, X. Visible-light-promoted
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(9) Fan, X. Z.; Rong, J. W.; Wu, H. L.; Zhou, Q.; Deng, H. P.; Tan, J.
D.; Xue, C. W.; Wu, L. Z.; Tao, H. R.; Wu, J. Eosin Y as a direct
hydrogen-atom transfer photocatalyst for the functionalization of C−
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(10) (a) Hein, J. E.; Fokin, V. V. Copper-catalyzed azide−
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ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science and
Technology of China (2017YFA0206903), the National
Natural Science Foundation of China (21861132004), the
Strategic Priority Research Program of the Chinese Academy
of Science (XDB17000000), Key Research Program of
Frontier Sciences of the Chinese Academy of Science
(QYZDY-SSW-JSC029), and K. C. Wong Education Founda-
tion.
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