Photoinduced Copper-Catalyzed Asymmetric Decarboxylative Alkynylation with Terminal Alkynes

Article abstract of DOI:10.1002/anie.202006317

We describe a photoinduced copper-catalyzed asymmetric radical decarboxylative alkynylation of bench-stable N-hydroxyphthalimide(NHP)-type esters of racemic alkyl carboxylic acids with terminal alkynes, which provides a flexible platform for the construction of chiral C(sp³)?C(sp) bonds. Critical to the success of this process are not only the use of the copper catalyst as a dual photo- and cross-coupling catalyst but also tuning of the NHP-type esters to inhibit the facile homodimerization of the alkyl radical and terminal alkyne, respectively. Owing to the use of stable and easily available NHP-type esters, the reaction features a broader substrate scope compared with reactions using the alkyl halide counterparts, covering (hetero)benzyl-, allyl-, and aminocarbonyl-substituted carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl alkynes, thus providing a vital complementary approach to the previously reported method.

Full text of DOI:10.1002/anie.202006317

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Photoinduced Copper-Catalyzed Asymmetric
Decarboxylative Alkynylation with Terminal Alkynes
Authors: Hai-Dong Xia, Zhong-Liang Li, Qiang-Shuai Gu, Xiao-Yang
Dong, Jia-Heng Fang, Xuan-Yi Du, Li-Lei Wang, and Xin-
Yuan Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006317
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10.1002/anie.202006317
Angewandte Chemie International Edition
RESEARCH ARTICLE
Photoinduced Copper-Catalyzed Asymmetric Decarboxylative
Alkynylation with Terminal Alkynes
Hai-Dong Xia,+ Zhong-Liang Li,+ Qiang-Shuai Gu,+ Xiao-Yang Dong,+ Jia-Heng Fang, Xuan-Yi Du, Li-
Lei Wang, and Xin-Yuan Liu*
[*]
Dr. H.-D. Xia,[+] X.-Y. Dong,[+] J.-H. Fang, X.-Y. Du, L.-L. Wang, Prof. Dr. X.-Y. Liu
Shenzhen Grubbs Institute and Department of Chemistry
Guangdong Provincial Key Laboratory of Catalysis
Southern University of Science and Technology
Shenzhen 518055 (China)
E-mail: liuxy3@sustech.edu.cn
Homepage: https://liuxy.chem.sustech.edu.cn
Dr. Z.-L. Li,[+] Dr. Q.-S. Gu[+]
Academy for Advanced Interdisciplinary Studies and Department of Chemistry
Southern University of Science and Technology
Shenzhen 518055 (China)
[+]
These authors contributed equally to this work.
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.XXXXX.
Abstract: We describe a photoinduced copper-catalyzed asymmetric
radical decarboxylative alkynylation of bench-stable N-
carbon centers via the prochiral alkyl radical intermediates.[3,4]
Recently, our group has discovered copper-catalyzed
a
hydroxyphthalimide(NHP)-type esters of racemic alkyl carboxylic
acids with terminal alkynes, providing a flexible platform for the
construction of chiral C(sp3)C(sp) bonds. Critical to the success of
this process are not only the use of the copper catalyst as a dual
photo- and cross-coupling catalyst but also the tuning of NHP-type
esters to inhibit the easily-occurring homodimerization of alkyl radical
and terminal alkyne, respectively. Owing to the use of stable and
easily available NHP-type esters, the reaction features a broader
substrate scope compared with their alkyl halide counterparts,
covering (hetero)benzyl-, allyl-, and aminocarbonyl-substituted
carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl
alkynes, thus constituting a vital complementary approach for the
previous methodology.
enantioconvergent radical C(sp3)–C(sp) cross-coupling of
racemic secondary alkyl halides and terminal alkynes (Scheme
1a).[5] During this course, a chiral alkaloid-derived multidentate
N,N,P-ligand is used for enhancing the reducing capability of
copper catalyst, thus converting alkyl halides to prochiral alkyl
radical species via a single electron transfer (SET) process.
However, the reaction has suffered from two major restrictions:
(1) Many alkyl halides require tedious synthesis; (2) some of the
alkyl halides are instable and do not provide the corresponding
a. Our prior work on asymmetric radical Sonogashira C–C coupling
OMe
H
N
R1
IIL1
R3
Cu
R3
L1
Cu(I)/
+
R1
R2
NH PAr2
R2 R1
R3
N
O
R2
X
()
Introduction
L1 (Ar = 3,5-tBu2C6H3)
X = Br, Cl
Limitation: tedious synthesis and/or instability of some alkyl halides
Transition-metal-catalyzed cross-coupling reactions have
evolved into a powerful tool to forge carboncarbon bonds and
revolutionized every aspect of chemistry.[1] While tremendous
progress has been made in the cross-coupling of aryl or vinyl
(pseudo)halides, the cross-coupling of alkyl (pseudo)halides
remains unexplored for a long time due to the difficult oxidative
addition and the facile -H elimination of alkyl metal complexes.[2]
Indeed, such transformations would potentially open up new
vistas in organic synthesis, especially when the stereochemistry
of the sp3-hybridized carbon centers can be controlled. In this
scenario, transition-metal-catalyzed enantioconvergent C(sp3)C
cross-coupling of racemic alkyl halides has received much
attention over the past two decades.[3,4] In particular, Fu and
others have pioneered this field by utilizing the chiral first-row
transition metal catalysis for the construction of stereogenic
b. Racemic decarboxylative alkynylation of NHP esters with prefunctionalized
alkynylation reagents
R
O
R1
O
R3
M
Br/ZnX
R1
N
Ni/Fe/Co
R2
+
R3
O
R2 R1
R3
R2
O

(
)
c. This work on asymmetric radical decarboxylative alkynylation with terminal alkynes
R
R1
O
60 examples
up to 81% yield
up to 99% ee
H
O
Cu L1
R2
R1
N
+
R3
O
R3
R2
O
()
Cu as a dual photo- and coupling catalyst
readily available and stable alkyl electrophiles
inhibition of the homodimerization of alkyl radical and terminal alkyne, respectively
broad scope compared with alkyl halide counterparts
Scheme 1. Asymmetric radical decarboxylative alkynylation.
1
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10.1002/anie.202006317
Angewandte Chemie International Edition
RESEARCH ARTICLE
chiral alkynes. These apparent limitations would thwart the wide
application of this methodology in organic synthesis. Given the
importance of chiral alkynes as versatile synthetic intermediates
and medicinally relevant molecules, the development of easily
available and stable alkyl electrophiles as alkyl halide surrogates
to enrich the synthetic toolbox for enantioconvergent C(sp3)–
C(sp) cross-coupling of terminal alkynes is highly desirable.
Alkyl carboxylic acids are cheap, highly stable and easily
available building blocks, and are among the most ubiquitous
organic molecules found in nature.[6] Great progress has been
recently made in the utility of carboxylic acids or their redox-active
esters (e.g., N-hydroxyphthalimide (NHP) ester) as radical
precursors in transition metal-catalyzed radical decarboxylative
cross-coupling reactions.[6,7] Despite these advances, the
exploration of the asymmetric variants for expedite access to
chiral CC/X bonds has been few and far between.[8] In 2016, Fu
and MacMillan jointly disclosed the first asymmetric
decarboxylative arylation by a cooperative photo- and nickel
catalysis.[8a] Subsequently, Reisman and Liu independently
developed the asymmetric decarboxylative vinylation and
cyanation of NHP esters utilizing either a nickel catalysis[8b] or a
cooperative photo- and copper catalysis,[8c] respectively. In light
of the urgent demand of new catalysis for asymmetric
decarboxylation, we wondered if our developed copper/N,N,P-
ligand catalyst[5] could be used for realizing an asymmetric
decarboxylative alkynylation of racemic carboxylic NHP esters.
Although Baran and others[9] have elegantly achieved the racemic
variants with prefunctionalized alkynylation partners, the
asymmetric transformation with easily available terminal alkynes
has never been reported, probably due to the challenging
stereocontrol over the highly reactive prochiral alkyl radical
intermediates (Scheme 1b). Another problem associated terminal
alkynes is the easily-occurring Glaser homocoupling of terminal
alkynes.[10] The success of this approach would provide a new
platform for the enantioconvergent radical decarboxylative
alkynylation reactions.
Based on the above-mentioned proposal, we began to
investigate the cross-coupling of racemic ester 1aa, prepared in
one step from commercially available 2-phenylpropanoic acid,
with phenylacetylene 2a (Table 1). However, screening of
different solvents and bases under blue LED irradiation in the
Table 1. Screening of reaction conditions.[a]
CuI (10 mol%), L1 (12 mol%)
H
Cs2CO3 (2.0 equiv.)
O
Ph
R
+
Ph
Ph
Blue LED (24 W)
PhCF3, rt
O
Ph
3
, 92% ee
1a
()-
2a
Ph
N
OMe
N
Ph
N
3'
NH PAr2
HN
N
O
PAr2
O
Ph
Ph
O
L1: (Ar = 3,5-tBu2C6H3)
L2: (Ar = 2,4,6-Me3C6H2)
L3, Ar = 3,5-tBu2C6H3
3''
redox-active NHP esters
O
N
O
O
O
N
OMe
F
Me
N
N
O
O
O
()-
()-1ad
1aa
Cl
()-1ab
()-1ac
Ph
Ph
O
O
O
O
N
O
Cl
Cl
Ph
Ph
N
N
O
N
O
O
Cl
()-1ae
()-1af
()-1ag
()-1ah
Entry
Conversion
Yield of 3
Yield of 3′
Yield of 3′′
()-1a
1
2
89%
83%
85%
80%
90%
47%
49%
53%
50%
55%
65%
87%
95%
92%
21%
12%
14%
21%
12%
20%
30%
37%
21%
30%
37%
58%
70%
64%
~30%
~30%
~30%
~30%
~30%
~10%
trace
trace
trace
trace
trace
trace
trace
trace
12%
19%
5%
()-1aa
()-1ab
()-1ac
()-1ad
()-1ae
()-1af
()-1ag
()-1ah
()-1ah
()-1ah
()-1ah
()-1ah
()-1ah
()-1ah
3
4
17%
11%
5%
5
6
At the beginning, we speculated that the chiral copper(I)
acetylide complex in situ generated from copper(I), terminal
alkyne and chiral ligand might directly reduce NHP esters to afford
alkyl radicals. Unfortunately, the initial attempts indicated very low
reaction efficiency, possibly due to the weak reducing capacity of
copper(I) acetylide. Notably, recent studies have demonstrated
that the copper(I) acetylide complex can be excited under visible
7
trace
trace
trace
trace
trace
trace
trace
trace
8
9[b]
10[c]
11[d]
12[e]
13[f]
14[g]
light irradiation, transforming to
a long-lived and strong
reductant.[11-13] We questioned whether the chiral copper(I)
acetylide complex could act as both the photocatalyst and the
cross-coupling catalyst to realize the asymmetric transformation.
As our continuous interest in Cu(I)-catalyzed asymmetric
[a] Reaction conditions: ()-1a (0.050 mmol), 2a (0.075 mmol.), CuI (10 mol%),
L1 (12 mol%), and Cs2CO3 (0.10 mmol, 2.0 equiv.) in PhCF3 (0.50 mL) at room
temperature under irradiation of blue LED (24 W) for 72 h under argon. Yields
of 3 and 3′′ were based on 1H NMR analysis of the crude product using CH2Br2
as an internal standard. Isolated yield of 3′ is shown. Ee value was determined
by HPLC analysis. [b] CuI (15 mol%) and L1 (18 mol%) were used. [c] 2a (0.10
mmol) with 1.0 mL of PhCF3 was used. [d] 2.5 equiv. of Cs2CO3 was used. [e]
3.0 equiv. of Cs2CO3 was used. [f] 3.5 equiv. of Cs2CO3 was used. [g] 4.0 equiv.
of Cs2CO3 was used.
reactions involving radicals,[5,14] we herein describe
photoinduced copper-catalyzed asymmetric radical
a
decarboxylative C(sp3)–C(sp) cross-coupling of racemic NHP
esters with terminal alkynes (Scheme 1c). Noteworthy is that this
strategy exhibits unique features in terms of tolerating substrates
that are challenging or even inapplicable to our previous
Sonogashira coupling of alkyl halides,[5] rendering it a valuable
alternative to the previous approach.
presence of CuI and L1 delivered the desired product 3 in poor
yield, albeit with excellent enantioselectivity, along with the
starting carboxylic acid via the hydrolysis of 1aa, the Glaser
homocoupling product 3′ and radical dimerization product[15] 3′′
(Tables S1 and S2 in Supporting Information). We then screened
various copper salts and cinchona alkaloid-derived N,N,P-ligands,
but the hydrolysis of 1aa and the dimerization process cannot be
Results and Discussion
2
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10.1002/anie.202006317
Angewandte Chemie International Edition
RESEARCH ARTICLE
inhibited (Table S3 and S4 in the Supporting Information). We
speculated that the low reaction efficiency and occurrence of the
dimerization reactions might be attributed to the reactivity of NHP
ester 1aa. We then coupled different type of N-hydroxy imides
with the carboxylic acid to achieve a good reaction efficiency.
After screening diverse esters 1aa1ah (Table 1, entries 28), we
were pleased to find that with N-hydroxy 2,3-naphthalimide(R =
NNaphth)-derived ester 1ah as the substrate, the reaction
efficiency was enhanced, and the dimerization products were also
inhibited (Table 1, entry 8). Further increasing either catalytic
loading of CuI and L1 or the amount of 2a could not improve the
reaction efficiency (entries 9 and 10). It is worth noting that
increasing the amount of Cs2CO3 to 3.5 equiv. could efficiently
improve the reaction efficiency and give 3 in 70% yield and 92%
ee (entry 13). No reaction occurred in the absence of copper or
Cs2CO3 and only trace amount of desired products was detected
in the absence of light or ligand, suggesting that all the
parameters are essential to the success of the asymmetric
alkynylation (Table S5 in the Supporting Information).
Table 2. Substrate scope of NHP-type esters.[a]
With the optimal reaction conditions established, the substrate
scope of racemic carboxylic acid-derived NHP-type esters was
then investigated (Table 2). We found that various substituents in
the alkyl branch of the NHP-type esters was compatible with the
reaction conditions and the alkynylation products 310 were
obtained in good yields and 9099% ee (Table 2a). Many
potentially reactive groups, such as chloride (7), ester (8), alkyne
(9), and terminal alkene (10), were left untouched. As for the aryl
ring, a range of NHP-type esters, including those having halides
(1114), methyl (15) or methoxyl (16) groups at different positions
(ortho, meta, or para) of phenyl rings and a naphthalene ring (17),
reacted smoothly to afford chiral alkynes in good yields and
excellent ee. Besides, for carboxylic acids commonly used as
anti-inflammatory drugs, such as ibuprofen, flurbiprofen,
pranoprofen and zaltoprofen, their NHP-type esters underwent
the reaction smoothly as well to generate the coupling products
1821 in good yields and 8898% ee (Table 2b). The late-stage
modification of natural product estrone was also feasible to give
the alkylation product 22 in 43% yield. Furthermore, NHP-type
esters containing heterocycles, such as pyridine, benzo[b]furan
and benzo[b]thiophene, also worked well to deliver 2325 in
excellent ee (Table 2c). Interestingly, the allylic and -
aminocarbonyl substrates were also found to be suitable for the
reaction to afford the expected products 2628 in good ee, albeit
with low yield (Table 2d). Unfortunately, the homobenzylic
substrate delivered a racemic coupling product 29, while the
tertiary substrate did no provide the desired product 30 (Table 2d).
These results are currently under further optimization in our lab.
Direct comparisons were also made between the NHP-type
esters and alkyl halides.[5] As such, the reaction of ortho-
substituted benzylic substrates provided the desired products 31
and 32 in good yields, respectively. In contrast, the ortho-
substituted benzyl halides always reacted in much lower
efficiency in our previous work[5] (Table 2e). Further, benzyl
halides with strong electron-withdrawing or -donating functional
groups at the para positions of phenyl rings and cyclic benzylic
halides are generally unstable, rendering them inapplicable to our
previous Sonogashira conditions.[5] To our delight, the desired
enantioenriched alkynes 3338 were successfully generated from
the decarboxylative alkynylation of the stable NHP-type esters in
6793% ee, but the yields are low for substrates with electron-
withdrawing groups.
[a] Reaction conditions: 1 (0.20 mmol), 2a (0.30 mmol), CuI (10 mol%), L1 (12
mol%), and Cs2CO3 (0.70 mmol) in PhCF3 (4.0 mL). Yield was determined after
isolation; Ee value was determined using HPLC analysis. [b] Reaction time is 4
d. [c] CuI (20 mol%) and L1 (24 mol%) in Et2O. [d] CuI (15 mol%) and L1 (18
mol%). [e] With L2 as the ligand and Et2O as the solvent. [f] Our recent reported
results of asymmetric Sonogashira reaction in parenthesis.ref. 5
Encouraged by the above results, we next examined the scope
of alkynes. A number of aryl alkynes proceeded smoothly to give
39–52 in good yields with excellent ee under the standard
conditions. Diverse functional groups such as methoxyl (39),
chloro (4143), bromo (44), fluoro (45), trifluoromethyl (46), nitrile
(47), formyl (48), methoxycarbonyl (49), pinacolborato (50) and
terminal alkyne (51) were well tolerated. The absolution
configuration of 39 was determined to be R by comparing its
HPLC spectrum and optical rotation with those reported in
literature[5] and the configurations were inferred accordingly. The
3
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10.1002/anie.202006317
Angewandte Chemie International Edition
RESEARCH ARTICLE
decarboxylative alkynylation was also applicable to heteroaryl
alkynes that contain medicinally relevant heterocycles, such as
Table 3. Substrate scope of alkynes.[a]
with propyne provided 64 in 76% ee, which is a key intermediate
in the synthesis of a drug lead (AMG 837, a G-protein coupled
receptor GPR40 agonist)[5,17] under slightly modified conditions.
Besides, the enantioenriched alkyne 39 could undergo either a
stereoselective partial or complete hydrogenation to afford chiral
Z-alkene 65 or alkane 66, respectively, without any loss of ee.
Thus, the asymmetric decarboxylative alkynylationwhen
combined with simple transformationsprovides an excellent
complementary strategy for the construction of chiral C(sp3)–
C(sp2) and C(sp3)–C(sp3) bonds from cheap and stable carboxylic
acids.
To demonstrate the practicality of this method, we next
developed a tandem one-pot procedure for direct use of readily
available racemic carboxylic acids in the reaction. Thus, the crude
esters obtained by coupling of carboxylic acids 67a and 67b with
68 were applied directly to the standard conditions without further
purification, delivering the chiral alkynes 4 and 18 with good
results, respectively (Scheme 2a). In addition, a large-scale
reaction of 1b and phenyl acetylene 2a was also performed to
deliver the desired product 4 in 58% yield with 97% ee (Scheme
2b).
a) One-pot synthesis
R2
R2
O
1) DMAP, DCC
CH2Cl2, 0 °C–rt;
COOH
+
HO N
2) standard
conditions
Ph
R1
R1
67a
67b
O
68
, R1 = H, R2 = Et
4
, 61%, 97% ee
(1 equiv.)
H
i
, R1 = Bu, R2 = Me
18, 55%, 90% ee
b) Large-scale synthesis
standard
conditions
O
+
Ph
NNaphth
Ph
Ph
2a
Ph
O
1b (1.8 g)
4, 58%, 98% ee
(1.5 equiv.)
Scheme 2. Synthetic applications.
a) TEMPO inhibiting experiment
Ph
2a
(1.5 equiv.)
O
standard conditions
+
Ph
NNaphth
Ph
TEMPO (1.0 equiv.)
Ph
O
Ph
Ph
1b
4, 0%
3', 30%
b) Radicl clock experiment
[a] Reaction conditions: 1 (0.30 mmol), 2 (0.20 mmol), CuI (10 mol%), L1 (12
mol%), and Cs2CO3 (0.70 mmol) in PhCF3 (4.0 mL). The yield was isolated and
the ee value was determined by HPLC. [b] CuI (15 mol%), L1 (18 mol%). [c] 1
(0.20 mmol), 2 (0.24 mmol), CuI (15 mol%), L1 (12 mol%), for 4 d. [d] CuI (15
mol%), L1 (12 mol%), and propyne (5.0 equiv.). [e] CuI (20 mol%), L3 (24
mol%), and propyne (5.0 equiv.).
standard
conditions
O
Ph
Ph
NNaphth
Ph
+
Ph
70
O
1c
69
, 10%
, 53%, 87% ee
c) Reaction with stoichiomeric copper acetylide and ligand effect
L1
, Cs2CO3 (3.5 equiv.)
O
Ph
+
thiophene (53 and 54), pyridine (55), and quinoline (56), affording
the desired chiral alkynes in excellent ee. Furthermore, the direct
decarboxylative alkynylation enabled a single-step access to a
patented mGluR modulator 57 in 93% ee. More significantly,
many aliphatic alkynes with different functional groups, such as
conjugated alkene (58), acetal (59), acetate (60), and even free
alcohol (61) reacted smoothly in this process. Trimethylsilyl
acetylene also worked well to provide 62 in 50% yield and 94%
ee. The direct incorporation of industrial feedstocks into organic
molecules for synthesis of complex synthetic intermediates or
medicinally relevant compounds is an important goal of chemical
research. As such, we were delighted to find that the industrially
relevant propyne,[16] was also suitable to provide 63 in 58% yield
and 93% ee. Furthermore, the direct decarboxylative alkynylation
Cu
Ph
Ph
NNaphth
PhCF3, rt, 3 d, blue LED
L1
Ph
O
4
(12 mol%)
L1 (0 mol%)
, 55%, 92% ee
1b
71 (1.5 equiv.)
4, 10% yield
Scheme 3. Control experiment for mechanistic investigation.
To gain some insight into the reaction mechanism, we carried
out a series of control experiments. When TEMPO was added
under the otherwise standard conditions, the reaction was
completely inhibited and only the Glaser reaction occurred to
provide 3′ (Scheme 3a). The reaction of radical clock substrate 1c
delivered the ring-opening/alkynylation product 69 in 10% yield
along with the alkynylation product 70 (Scheme 3b). These
4
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10.1002/anie.202006317
Angewandte Chemie International Edition
RESEARCH ARTICLE
experiments demonstrated that a radical process might be
involved in this reaction. The replacement of CuI and
phenylacetylene 2a with stoichiometric copper acetylide 71 under
the otherwise identical conditions provided the desired product 4
in 55% yield and 92% ee, showing that 71 might be involved in
the process. Only 10% yield of 4 was observed in the absence of
ligand, indicating that the ligand significantly promoted the
transformation (Scheme 3c).
Scheme S1 in in the Supporting Information for proposed model
in the asymmetric induction).
CuI
R2
base
Ph
L1
R1
L1CuI
Ph
II
L1
Cu
Ph
It is known that the copper acetylide complex can be
photoexcitated with photons of relatively low energy.[12]
Fluorescence quenching experiments revealed that the excited
copper acetylide was quenched by the NHP-type ester 1b rather
than 2a, indicating a possible SET process between the NHP-type
esters and the excited copper acetylide (Figure 1a and 1b). This
process was also supported by the cyclic voltammetry study,
which showed that the literature reported redox potential (2.048
V vs SCE in CH3CN)[12d] of the excited copper acetylide 71 is
strong enough to reduce the ester 1b (1.174 V vs SCE in CH3CN,
Figure S1 in the Supporting Information). Further fluorescence
quenching experiments demonstrated that the NHP-type esters
1aa1ae quenched the excited copper acetylide more efficiently
than 1af1ah, which might cause higher concentration of CuII
acetylide and benzylic radical IV (Scheme 4, Figure 1c).
Accordingly, fast radical-radical homocoupling might be favored
to provide 3′′, and the left CuII acetylide might have to undergo
Glaser coupling to deliver product 3′ as observed during the
condition optimization (Table 1).[10,15] However, too low quenching
efficiency may cause a low reaction efficiency and 1ah is the most
suitable NHP-type ester for the reaction.
III
L1CuI
Ph
R1 R2
IV
I
O
h
N
I
*
L1
Cu
Ph
O
1
CO2
II
Scheme 4. Mechanistic proposal.
Conclusion
In summary, we have described
a strategy for direct
asymmetric radical decarboxylative alkynylation of NHP-type
esters with terminal alkynes utilizing a photoinduced copper
catalysis. One striking feature of this strategy is the dual roles of
the copper catalyst as both the photo- and the cross-coupling
catalysts. The NHP-type esters are tuned to inhibit the easily-
occurring Glaser reaction, thus achieving good reaction efficiency.
Owing to the ready availability of carboxylic acids and the high
stability of NHP-type esters, this strategy largely expands the
substrate scope compared with that using the corresponding alkyl
halide counterparts. Therefore, it provides an efficient and general
synthetic tool for not only chiral C(sp3)–C(sp) but also chiral
C(sp3)–C(sp2/sp3) bond formations when allied with follow-up
transformations. Further studies toward the development of direct
asymmetric radical decarboxylative reactions with other
nucleophiles are ongoing in our laboratory.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos. 21722203, 21831002, and 21801116),
Guangdong Provincial Key Laboratory of Catalysis (No.
2020B121201002), Guangdong Innovative Program (No.
2019BT02Y335), Shenzhen Nobel Prize Scientists Laboratory
Project (No. C17783101) and SUSTech Special Fund for the
Construction of High-Level Universities (No. G02216303) are
gratefully acknowledged. The authors acknowledge the
assistance of SUSTech Core Research Facilities.
Figure 1. Fluorescence quenching experiments. (a) copper acetylide emission
quenching by 1b. (b) copper acetylide emission quenching by 2a. (c) quenching
efficiency with 1aa1ah.
Based on these results and previous reports,[5,12] we proposed
a possible mechanism as shown in Scheme 4. CuI catalyst,
acetylene and the ligand L1 reacted in the presence of Cs2CO3 to
generate the intermediate I,[14h] which was directly excited to give
the complex II. Subsequently, the excited copper acetylide II can
transfer an electron to NHP-type ester 1 to deliver the CuII
complex III. Meanwhile, the formed anionic radical of NHP-type
ester undergoes a radical decarboxylation process to generate
the radical intermediate IV. This intermediate would undergo a
C(sp3)–C(sp) bond formation with III, providing chiral alkynes and
releasing the L1CuI complex for the next catalytic cycle (See
Keywords: alkynylation • asymmetric radical reaction • copper •
decarboxylation • photocatalysis
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6
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RESEARCH ARTICLE
Entry for the Table of Contents
R
O
R1
OMe
N
L*
Cu
O
H
+
R1
N
N
R2
O
R3
R3
R2
O
NH PAr2
60 examples
up to 81% yield
up to 99% ee
()
O
Cu as a dual photo- and coupling catalyst
readily available and stable alkyl electrophiles
broad scope compared with alkyl halide counterparts
L* (Ar = 3,5-tBu2C6H3
)
inhibition of homodimerization of alkyl radical and terminal alkyne, respectively
Chiral copper dual catalysis: A photoinduced asymmetric radical decarboxylative alkynylation of bench-stable racemic carboxylic
acid derivatives with easily available terminal alkynes is accomplished, providing expedient access to diverse enantioenriched
alkynes. The chiral copper catalyst serves as a dual photo- and cross-coupling catalyst to achieve the challenging stereocontrol over
the highly reactive prochiral alkyl radical intermediates.
7
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