Copper-catalysed photoinduced decarboxylative alkynylation: a combined experimental and computational study

Article abstract of DOI:10.1039/d0sc02213f

Redox-active esters (RAEs) as alkyl radical precursors have demonstrated great advantages for C-C bond formation. A decarboxylative cross-coupling method is described to afford substituted alkynes from various carboxylic acids using copper catalysts CuCl and Cu(acac)₂. The photoexcitation of copper acetylides with electron-rich NEt₃as a ligand provides a general strategy to generate a range of alkyl radicals from RAEs of carboxylic acids, which can be readily coupled with a variety of aromatic alkynes. The scope of this cross-coupling reaction can be further expanded to aliphatic alkynes and alkynyl silanes using a catalytic amount of preformed copper-phenylacetylide. In addition, DFT calculations revealed the favorable reaction pathway and that the bidentate acetylacetonate ligand of the copper intermediate plays an important role in inhibiting the homo-coupling of the alkyne.

Full text of DOI:10.1039/d0sc02213f

Chemical
Science
View Article Online
View Journal
EDGE ARTICLE
Copper-catalysed photoinduced decarboxylative
alkynylation: a combined experimental and
computational study†‡
Cite this: DOI: 10.1039/d0sc02213f
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
*
*
Shengyang Ni
Yu Mao, Wenxuan Zhao, Shuo Lu, Lei Yu, Yi Wang,
and Yi Pan
Yong Liang,
Redox-active esters (RAEs) as alkyl radical precursors have demonstrated great advantages for C–C bond
formation. A decarboxylative cross-coupling method is described to afford substituted alkynes from
various carboxylic acids using copper catalysts CuCl and Cu(acac)2. The photoexcitation of copper
acetylides with electron-rich NEt3 as a ligand provides a general strategy to generate a range of alkyl
radicals from RAEs of carboxylic acids, which can be readily coupled with a variety of aromatic alkynes.
The scope of this cross-coupling reaction can be further expanded to aliphatic alkynes and alkynyl
silanes using a catalytic amount of preformed copper-phenylacetylide. In addition, DFT calculations
revealed the favorable reaction pathway and that the bidentate acetylacetonate ligand of the copper
intermediate plays an important role in inhibiting the homo-coupling of the alkyne.
Received 20th April 2020
Accepted 20th April 2020
DOI: 10.1039/d0sc02213f
rsc.li/chemical-science
difunctionalisation of alkenes and alkynes using Cu(dap)Cl2 as
a photocatalyst.11 Hwang discovered copper acetylide complexes
as a photosensitiser for various coupling reactions.12 Recently,
Lalic achieved the coupling products of alkyl iodides and
terminal alkynes via photoexcited Cu(I)-acetylide combined
with a substituted terpyridine ligand (Scheme 1B).13
Introduction
Carbon–carbon triple bonds are versatile intermediates for
diverted transformations.1 Serving as both nucleophiles and
electrophiles, alkynes are broadly employed in organic
synthesis, materials science,2 chemical biology,3 and drug
discovery.4 Among many metal-catalysed cross-coupling strate-
gies for the construction of the Csp–C bond, the Sonogashira
reaction was the most renowned approach to access alkyl
substituted alkynes (Scheme 1A).5 Under basic conditions,
copper acetylides generated in situ from Cu(I) salts and terminal
alkynes undergo metal-catalysed cross-coupling reactions.6
However, the Sonogashira reaction usually requires function-
alised electrophiles with adequate leaving groups and Pd
complexes as catalysts.7 The development of mild and general
cross-coupling strategies for copper acetylides without precious
catalysts is still a great challenge and in high demand.
Copper has merged into the recent evolution of visible-light
photoredox catalysis which led to a paradigm shi in organic
synthesis.8 Recently, photoexcitation of copper complexes has
been applied to the formation of carbon–carbon and carbon–
heteroatom bonds.9 Fu and Peters discovered a photoinduced
copper-mediated C–N coupling reaction.10 Reiser developed
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced
Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210023, China. E-mail: yiwang@nju.edu.cn; yongliang@nju.edu.cn
† Dedicated to the 100th anniversary of the School of Chemistry and Chemical
Engineering, Nanjing University.
Scheme 1 (A) Sonogashira coupling; (B) photoinduced coupling of
alkyl iodides via Cu-terpyridine acetylides; (C) decarboxylative alky-
nylation via Cu(Et3N)(acac) acetylides.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc02213f
This journal is © The Royal Society of Chemistry 2020
Chem. Sci.

View Article Online
Chemical Science
Edge Article
In comparison with alkyl halides, inexpensive carboxylic subsequent alkyl radical formation. Therefore, choosing
acids are widely accessible and used for decarboxylative reac- competent ligands is essential to activate redox-active esters for
tions.14 Notably, recent methods using redox-active esters for the realisation of copper-catalysed decarboxylative alkynylation.
decarboxylative cross-coupling reactions have been developed;15
Aer a comprehensive survey of metal salts, ligands and
in particular, decarboxylative alkynylation of RAEs has been bases (Table 1 and also see the ESI‡), the optimised reaction
reported by Weix,15e Baran,15f and Chen15t using prefunctional- conditions have been selected as alkyne 1 (1.0 equiv.), RAE 2 (1.5
ised alkynyl sources, including alkynyl bromides, alkynyl zinc equiv.) with 10 mol% each of Cu(acac)2 and CuCl, and Et3N (2.5
reagents and alkynyl benziodoxolone. Fu developed a photo- equiv.) in THF under the irradiation of 90 W blue LEDs. With
catalysed decarboxylative cross-coupling reaction using 95% conversion of 2, the desired decarboxylative alkynylation
terminal alkynes and redox-active esters of amino-acids, but product 3 in 72% and 22% of the homo-coupling byproduct
only a limited scope of substrates was demonstrated.15s
were afforded (Table 1, entry 1). In the catalytic system, CuCl
Drawing inspiration from photosensitive copper acetylide as could be replaced by copper powder to give similar results (entry
an intermediate for sp3–sp bond formation, we envisioned RAEs 2). When Cu(acac)2 was replaced by other transition metal salts,
of carboxylic acids to be widely accessible surrogates of alkyl Fe(acac)2 provided low yield of the cross-coupling product (entry
iodides for cross-coupling of terminal alkynes. In the presence 3). Co(acac)2 and Ni(acac)2 demonstrated similar results to
of a weak base, photoexcitation of copper acetylide would Cu(acac)2 (entries 4 & 5). Using Zn(acac)2, the product 3 could
trigger the decarboxylative fragmentation of RAEs followed by only be obtained in moderate yield with a considerable amount
cross-coupling to provide alkylated alkynes. Herein, we report of homo-coupling product (entry 6). The previously reported
a photoinduced decarboxylative alkynylation of redox-active terpyridine ligand was found incompatible with this decarbox-
esters using inexpensive copper catalysts (Scheme 1C).
ylative alkynylation protocol, and only 8% of the product was
detected with 72% of the homo-coupling product (entry 7). In
the absence of Cu(acac)2, low yield of 3 was obtained with
a large amount of the homo-coupling product (entry 8). These
results demonstrated that the presence of the acetylacetonate
anion is crucial mainly for inhibiting the homo-coupling of the
alkyne. Further control reactions illustrated that in the absence
of the Cu(I) salt, this cross-coupling reaction could not proceed
(entry 9). By removing Et3N or switching to K2CO3, the reaction
failed to proceed (entries 10 & 11). Using a different light source,
20 W compact uorescent light, afforded slightly lower yield
(entry 12). The reaction was completely shut down in darkness
(entry 13). In the attempts for non-aryl substituted alkynes, no
reaction was detected under the standard conditions A,
primarily for the unmatched energy transfer between visible
light and unconjugated copper acetylides (Table 2, entry 2).
Further study revealed that by simply adding a catalytic amount
of phenyl copper acetylide as the photocatalyst, the alkylated
ethynylsilane was generated in 95% yield (entry 1). Other
components in the conditions are proven to be necessary. No
reaction occurred or very low yield was obtained without CuCl,
Cu(acac)2, Et3N or light (entries 3–6). Thus, the standard
conditions A and B were selected to explore the scope of aryl and
non-aryl alkynes, respectively.
Results and discussion
To determine the suitable conditions for copper acetylide-
initiated radical alkylation of alkynes, we rst tried the cross-
coupling of a cyclohexanecarboxylic acid derived redox-active
ester and 4-methylphenylacetylene under Lalic's conditions.
However, the reaction resulted in no desired cross-coupling
product and only a homo-coupling product was generated
(Scheme 2A). We speculated that the excited copper acetylide
with the tri-tBu-TERPY ligand could not efficiently transfer an
electron to the redox-active ester, making alkyl radical genera-
tion unsuccessful. To test this hypothesis, we calculated the
thermodynamics of the electron transfer processes from the
excited copper species to isopropyl iodide and the isobutyric
acid derived redox-active ester, respectively.16 As shown in
Scheme 2B, electron transfer from the Cu–terpyridine complex
to alkyl iodide is exergonic, with a reaction free energy of
ꢀ4.4 kcal molꢀ1. In contrast, the process for the redox-active
ester is endergonic (5.5 kcal molꢀ1), inhibiting the
To explore the scope of this decarboxylative alkynylation,
a range of primary, secondary and tertiary redox-active esters
underwent radical cross-coupling sequence with 4-methyl-
phenylacetylene under mild irradiation conditions (Scheme
3A). Carboxylic acids bearing cyclic hydrocarbons and hetero-
cycles were tolerated in this transformation (3–9 & 11–17).
Highly strained alkynyl cyclic products were obtained from the
corresponding commercially available carboxylic acids (11–15),
Notably, the a-oxygen and nitrogen substituted carboxylic acids
(16–17) that were considered inert in radical reactions can also
provide moderate yields. To demonstrate the utility of this
cross-coupling protocol, we applied the standard conditions to
a range of natural and pharmacal products (Scheme 3A). Searic
acid (19), arachidonic acid (20), L-glutamic acid (21), pinonic
Scheme
interpretation.
2 (A) Initial experimental test and (B) computational
Chem. Sci.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
Table 1 Control experiments for decarboxylative alkynylation with aryl alkynes in 0.1 mmol scale
Convention
of 2
Entry
Deviation from the reaction conditions
Homocoupling of 2a
Yield of 3a
1
None
95%
92%
83%
90%
98%
87%
91%
86%
0%
22%
16%
36%
18%
18%
32%
72%
62%
0%
72%b
67%
12%
68%
74%
36%
8%
2c
3
CuCl to Cu powder
Cu(acac)2 to Fe(acac)2
Cu(acac)2 to Co(acac)2
Cu(acac)2 to Ni(acac)2
Cu(acac)2 to Zn(acac)2
Cu(acac)2 to tBu3-TERPY
Without Cu(acac)2
Without CuCl
4
5
6
7
8
9
21%
0%
10
11
12
13
Without Et3N
Et3N to K2CO3
Blue LED to 20 W CFL
In darkness
0%
0%
92%
0%
0%
0%
10%
0%
0%
0%
68%
0%
a
Crude yields determined by 1H NMR spectroscopy using dibromomethane as an internal standard. b 69% isolated yield. c Copper powder treated
with hydrochloric acid.
Table 2 Control experiments for decarboxylative alkynylation with
non-aryl alkynes in 0.1 mmol scale
alkynylation reaction. Using a catalytic amount of copper-
phenylacetylide as the photocatalyst, the alkylations of non-
aryl alkynes could proceed smoothly using LED light (Scheme
3C). To examine the scope of aliphatic alkynes, bicyclic (40–46),
cyclohexyl (47–52), linear (53) and adamantane (54) substituted
carboxylic acids were attempted under conditions B. Both linear
and cyclic alkyl tethered alkynes transformed into the alkylated
products (42–44). Terminal alkynes bearing silyl (40, 41, 47 and
53), alkenyl (45), hydroxyl (46), epoxyl (49), acetal (50) and amide
(51) groups were susceptible to the reaction conditions to ach-
ieve the corresponding products in good to excellent yields.
Contraception drug 19-morethindrone acetate was also sub-
jected to the standard conditions to furnish the alkylated
derivative in 78% yield (52).
Entry
Deviation from the reaction conditions
Yielda
1
2
3
4
5
6
None
95%
0%
10%
5%
0%
0%
Without copper-phenylacetylide
Without CuCl
Without Cu(acac)2
Without Et3N
Scalability was also evaluated, and the reaction was found to
proceed smoothly to deliver product 55 on a gram-scale in 70%
yield (Scheme 3D). In addition, the redox-active ester could be
prepared in situ and afford the cross-coupling product 3 in
a one-pot fashion (Scheme 3E).
In darkness
a
Crude yields determined by 1H NMR spectroscopy using
dibromomethane as an internal standard.
To gain insight into the mechanism and understand the
ligand effects in this reaction, computational studies are con-
ducted using DFT calculations.16 The reaction between an
aromatic alkyne (Ar ¼ Ph) and the redox-active ester of
carboxylic acid (R ¼ i-Pr) is chosen as the model system.
Organometallic intermediates and transition states with various
coordination numbers of NEt3 are optimised, with the lowest
state shown in this study. The reaction pathways are summar-
ised in Scheme 4. First, Cu(I) acetylide is generated with the
assistance of NEt3. Excitation with blue light promotes Cu(I)
acetylide to its triplet state. Subsequently, excited Cu(I) acetylide
transfers an electron to activate N-acyloxyl phthalimide into its
acid (22), chloroambucil (23) and dehyrocholic acid (24) derived
esters were compatible to afford alkynylated derivatives.
We next employed cyclohexyl and piperidinyl substituted
esters to examine the scope of aryl alkynes (Scheme 3B). Both
electron-donating and electron-withdrawing groups were toler-
ated under the same conditions (25–32 & 36). Naphthyl (33),
thiophene (34), pyridyl (35), indoyl (37), carbazoyl (38) and
benzothiozyl (39) groups were applicable for generating the
desired products in good yields. Notably, no alkylation occurred
for unprotected N–H (37 & 38).
With a slight variation in the optimised conditions, we
further expanded the scope of alkynes for this decarboxylative
This journal is © The Royal Society of Chemistry 2020
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Scheme 3 (A–C) Substrate scope of the decarboxylative alkynylation; (D) gram-scale reaction; (E) one-pot reaction. [a] The reaction was
conducted under standard conditions A; [b] the reaction was conducted under standard conditions B; [c] the ratios of diastereomers were
1
determined by H NMR.
radical anion, accompanied by its oxidation to the Cu(II) acety- exergonic reduction of the redox-active ester (ꢀ12.3 kcal molꢀ1
,
t
lide cation (Scheme 4A).17 In contrast with Bu3-TERPY (ender- Scheme 4A), which can be attributed to the electron-rich nature
gonic by 5.5 kcal molꢀ1, Scheme 2B), the NEt3 ligand enables of NEt3 in stabilising cationic Cu(II) species. The reaction of
Chem. Sci.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
Scheme 4 DFT calculations of the reaction pathways. Numbers associated with each molecule are relative Gibbs free energy in THF. Note that in
each part the zero points of energy are different. (A) Formation, excitation, and electron transfer of Cu(I) acetylide. (B) Fragmentation of the N-
acyloxyl phthalimide radical anion. (C) Ligand exchange, radical addition to Cu(II) acetylide, and reductive elimination to generate the cross-
coupling product. (D) Competing pathways without the participation of Cu(acac)2. (E) Homo-coupling side reaction pathways start from Int6-
acac.
This journal is © The Royal Society of Chemistry 2020
Chem. Sci.

View Article Online
Chemical Science
Edge Article
propyne as a model of aliphatic alkyne is also investigated. elevates the homo-coupling barriers and remarkably promotes
Compared to phenyl acetylide, excitation of methyl substituted the formation of cross-coupling products.
Cu(I) acetylide Int3-Me is more endergonic (75.1 kcal molꢀ1
,
Based on the above experimental and computational
Scheme 4A), which is outside the blue light energy range (l ¼ evidence, a plausible mechanism is suggested (Scheme 5). First,
400 nm, hn ¼ 71.5 kcal molꢀ1). Therefore, a catalytic amount of in the presence of NEt3, Cu(I) complex A is formed which reacts
Cu(I) phenylacetylide (Int3) is required to facilitate the photo- with the alkyne to afford photosensitive copper(I) acetylide B.
redox process, in accordance with experimental ndings The photoexcitation of B furnishes copper acetylide C, which
(Scheme 3C). In the case of non-aryl alkynes as the substrate, undergoes the SET process with a redox-active ester to afford
aer the photoexcitation of catalyst Int3 and subsequent elec- a radical anion of the RAE and Cu(II)-acetylide D. Subsequent
tron transfer to the redox-active ester, an exchange reaction decarboxylative fragmentation provides an alkyl radical. Ligand
(Scheme 4A) between the cationic Cu(II) species Int5 and Cu(I) exchange between Cu(II)-acetylide D and Cu(acac)2(NEt3) gives
methylacetylide (Int3-Me) will occur to regenerate photocatalyst the key copper intermediate E. Finally, the addition of the alkyl
Int3 and to form Int5-Me as the precursor for the alkynylation of radical to E gives Cu(III) intermediate F, followed by reductive
aliphatic alkynes.16
elimination to furnish the cross-coupling product and G.
The subsequent fragmentation of the N-acyloxyl phthalimide Hence, several critical factors are pointed out for the realisation
radical anion leads to the iso-butyryloxy radical, which of the cross-coupling reaction. First, a conjugated aromatic
undergoes fast decarboxylation to afford the iso-propyl radical alkyne is required for the photoexcitation of Cu(I) acetylides
(Scheme 4B).18 Then the Cu(II) acetylide cation undergoes ligand within the visible light energy range. Second, the electron-rich
exchange with NEt3$HCl and Cu(acac)2 to generate intermediate ligand NEt3 promotes the electron transfer from copper acety-
Int6-acac. The addition of the iso-propyl radical to Int6-acac lides to redox-active esters. Finally, the bidentate acetylaceto-
forms the Cu(III) intermediate8,19 with an activation barrier of nate ligand effectively intervenes in the generation of bi-copper
6.8 kcal molꢀ1, followed by a facile reductive elimination to complexes, which prohibits the formation of undesired homo-
produce the cross-coupling product and the regeneration of the coupling byproducts.
Cu catalyst (Scheme 4C).20 The overall rate-limiting step aer
photoexcitation is the fragmentation of the N-acyloxyl phthali-
mide radical anion (14.0 kcal molꢀ1, Scheme 4B), consistent
with experimental results that reactions proceed smoothly at
room temperature.
Experimental
Standard conditions for decarboxylative alkynylation with aryl
alkynes (conditions A)
To elucidate the crucial role of Cu(acac)2 in the success of
this reaction, we investigated several possible competing path-
ways that may exist in this system. Since the homo-coupling of
alkyne is found to be the major side reaction, this competing
pathway is also calculated for both with and without Cu(acac)2.
As shown in Scheme 4D, radical addition barriers are only
slightly higher without Cu(acac)2. The homo-coupling pathway
via a bi-copper complex21 Int10-2Cl has much lower activation
free energy (transition state TS5-2Cl, 3.6 kcal molꢀ1) than that of
the radical addition via the transition state TS3-Cl
(8.0 kcal molꢀ1), which will lead to the cross-coupling product.
This is in agreement with experimental ndings that homo-
coupling products will dominate with CuCl as the only cata-
lyst. Scheme 4E shows homo-coupling pathways starting from
Int6-acac. Three possible bi-copper complexes can be formed
with different ligands. However, their reductive elimination
barriers (8–15 kcal molꢀ1) are all higher than those for the iso-
propyl radical addition to Int6-acac (6.8 kcal molꢀ1, Scheme
4C). To rationalise this result, we noticed that the bidentate
nature22 of the acetylacetonate ligand causes Int6-acac to be
four-coordinated. Unlike the three-coordinated Int6-Cl inter-
mediate, it is required for Int6-acac to dissociate the NEt3 ligand
prior to the bi-copper complex formation, which is endergonic
by 6.9 kcal molꢀ1 (Scheme 4E). Meanwhile, the ligand exchange
to generate Int6-Cl is also endergonic. As a result, three possible
combinations of Int60-acac and Int6-Cl are all energetically
disfavored, making the relative dominance of the two pathways
(homo-coupling versus cross-coupling) reverse. Therefore, the
In a glovebox, redox active esters (0.15 mmol, 1.5 equiv.),
cuprous chloride (10 mol%), cupric acetylacetonate (10 mol%),
terminal alkyne (0.1 mmol, 1.0 equiv.), triethylamine (2.5
equiv.) and anhydrous THF (2 mL) were added. A tube was set
between two lamps (10 cm away from the lamp, 90 W each) and
the mixture was stirred at room temperature (with a fan to cool
down the reaction) for 16 h. The solvent was removed under
Scheme 5 The catalytic cycle for the copper-catalysed photoinduced
decarboxylative alkynylation and the important role of NEt3 and ace-
bidentate acetylacetonate ligand of the copper intermediate tylacetonate ligands in the reaction mechanism.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
vacuum. The crude product was puried by column chroma- afford the corresponding alkyne (silica, 0–100% EtOAc/
tography or preparative TLC to afford the corresponding alkyne petroleum ether).
(silica, 0–100% EtOAc/petroleum ether).
Conclusions
Standard conditions for decarboxylative alkynylation with
non-aryl alkynes (conditions B)*
In summary, we have developed a decarboxylative cross-
coupling method to access alkyl substituted alkynes. The
photoexcitation of copper acetylide complexes provides
a feasible strategy to generate a range of alkyl radicals from
readily available carboxylic acid derivatives without the use
noble metal photocatalysts, which can be successfully applied
in the copper-catalysed cross-coupling reaction with a broad
range of alkynes. In addition, DFT calculations revealed that
NEt3 and acetylacetonate ligands are crucial for the catalytic
cycle. Further study of RAE-initiated cross-coupling is underway
in our laboratory.
In a glovebox, redox active esters (0.15 mmol, 1.5 equiv.),
cuprous chloride (10 mol%), cupric acetylacetonate (10 mol%),
and copper phenylacetylide (10 mol%) were mixed in a sealed
culture tube. Terminal alkyne (0.1 mmol, 1.0 equiv.), triethyl-
amine (2.5 equiv.) and anhydrous THF (2 mL) were added in
sequence. A tube was set between two lamp (10 cm away from
the lamp, 90 W each) and the mixture was stirred at room
temperature (with a fan to cool down the reaction) for 16 h. The
solvent was removed under vacuum. The crude product was
puried by column chromatography or preparative TLC to
afford the corresponding alkyne (silica, 0–100% EtOAc/
petroleum ether). *Note: a small amount (5%) of the alkyl- Conflicts of interest
ation product of phenylacetylene was observed in the crude
reaction mixture.
There are no conicts to declare.
General procedure for decarboxylative alkynylation with aryl
alkynes (gram scale)
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21772085, 21803030, and 21971107),
the Fundamental Research Funds for the Central Universities,
the National Thousand Young Talents Program, the Jiangsu
Innovation & Entrepreneurship Talents Plan, and the NSF of
Jiangsu Province (BK20170631) in China. The numerical
calculations in this paper have been done on the computing
facilities in the High Performance Computing Centres of
Nanjing University and Collaborative Innovation Centre of
Advanced Microstructures and Collaborative Innovation Center
of Solid-State Lighting and Energy-Saving Electronics.
Redox active esters (15 mmol, 1.5 equiv.), cuprous chloride
(10 mol%) and cupric acetylacetonate (10 mol%) were mixed in
a sealed ask with an argon balloon. Then anhydrous THF (50
mL) was added. Terminal alkyne (10 mmol, 1.0 equiv.) and
triethylamine (2.5 equiv.) were added in sequence. A tube was
set between two lamps (10 cm away from the lamp, 90 W each)
and the mixture was stirred at room temperature (with a fan to
cool down the reaction) for 16 h. The solvent was removed
under vacuum. The crude product was puried by column
chromatography to afford the corresponding alkyne (silica, 0–
100% EtOAc/petroleum ether).
Notes and references
General procedure for in situ activation of carboxylic acids in
decarboxylative alkynylation
1 P. J. Stang and F. Diederich, Modern Acetylene Chemistry,
Wiley-VCH, Weinheim, 1995.
2 Y. Liu, J. W. Y. Lam and B. Z. Tang, Nat. Sci. Rev., 2015, 2,
493–509.
3 J. C. Jewett and C. R. Bertozzi, Chem. Soc. Rev., 2010, 39,
1272–1279.
4 P. Thirumurugan, D. Matasiuk and K. Jozwiak, Chem. Rev.,
2013, 113, 4905–4979.
A culture tube was charged with carboxylic acid (0.15 mmol, 1
equiv.) and N-hydroxyphthalimide (0.165 mmol, 1.1 equiv.).
Dichloromethane was added (1.5 mL, 0.1 M), and the mixture
was stirred vigorously. Then, N,N0-diisopropylcarbodiimide
(DIC, 0.165 mmol, 1.1 equiv.) was added dropwise via a syringe,
and the mixture was stirred until the acid was consumed
(determined by TLC). Aer consumption of all starting mate-
ꢁ
rials, the solvent was removed on a rotary evaporator at 35 C
5 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 16, 4467–4470.
under reduced pressure and dried on a high-vacuum line for at
least 5 minutes to remove residual CH2Cl2. Next, the tube was
moved into a glovebox. Cuprous chloride (0.01 mmol, 10 mol%)
and cupric acetylacetonate (0.01 mmol, 10 mol%) were mixed in
a sealed tube. Terminal alkyne (0.1 mmol, 1.0 equiv.), triethyl-
amine (0.25 mmol, 2.5 equiv.) and anhydrous THF (2 mL) were
added in sequence. A tube was set between two lamps (10 cm
away from the lamp, 90 W each) and the mixture was stirred at
room temperature (with a fan to cool down the reaction) for
16 h. The solvent was removed under vacuum. The crude
product was puried by column chromatography or PTLC to
6 (a) M. Eckhardt and G. C. Fu, J. Am. Chem. Soc., 2003, 125,
13642–13643; (b) W. Shi, Y. Luo, X. Luo, L. Chao, H. Zhang,
J. Wang and A. Lei, J. Am. Chem. Soc., 2008, 130, 14713–
14720; (c) L. Su, J. Dong, L. Liu, M. Sun, R. Qiu, Y. Zhou
and S.-F. Yin, J. Am. Chem. Soc., 2016, 138, 12348–12351;
(d) X.-Y. Cui, Y. Ge, S. M. Tan, H. Jiang, D. Tan, Y. Lu,
R. Lee and C.-H. Tan, J. Am. Chem. Soc., 2018, 140, 8448–
8455; (e) X.-Y. Dong, Y.-F. Zhang, C.-L. Ma, Q.-S. Gu,
F.-L. Wang, Z.-L. Li, S.-P. Jiang and X.-Y. Liu, Nat. Chem.,
2019, 11, 1158–1166.
This journal is © The Royal Society of Chemistry 2020
Chem. Sci.

View Article Online
Chemical Science
Edge Article
7 (a) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874–
922; (b) R. Chinchilla and C. Najera, Chem. Soc. Rev., 2011,
40, 5084–5121.
8 A. Hossain, A. Bhattacharyya and O. Reiser, Science, 2019,
364, eaav9713.
F.-F. Zhang and H.-J. Xu, Org. Lett., 2013, 15, 1472–1475; (f)
C. Ye, Y. Li and H. Bao, Adv. Synth. Catal., 2017, 359, 3720–
3724; (g) C. Yang, J.-D. Yang, Y.-H. Li, X. Li and
J.-P. Cheng, J. Org. Chem., 2016, 81, 12357–12363.
15 (a) J. T. Edwards, R. R. Merchant, K. S. McClymont,
K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A. Shaw,
D.-H. Bao, F.-L. Wei, T. Zhou, M. D. Eastgate and
P. S. Baran, Nature, 2017, 545, 213–218; (b) T. Chen,
L. M. Barton, Y. Lin, J. Tsien, D. Kossler, I. Bastida, S. Asai,
C. Bi, J. S. Chen, M. Shan, H. Fang, F. G. Fang, H.-w Choi,
L. Hawkins, T. Qin and P. S. Baran, Nature, 2018, 560, 350–
354; (c) A. Fawcett, J. Pradeilles, Y. Wang, T. Mutsuga,
E. L. Myers and V. K. Aggarwal, Science, 2017, 357, 283–
286; (d) T. Qin, J. Cornella, C. Li, L. R. Malins,
J. T. Edwards, S. Kawamura, B. D. Maxwell, M. D. Eastgate
and P. S. Baran, Science, 2016, 352, 801–805; (e) L. Huang,
A. M. Olivares and D. J. Weix, Angew. Chem., Int. Ed., 2017,
56, 11901–11905; Angew. Chem., 2017, 129, 12063–12067; (f)
J. M. Smith, T. Qin, R. R. Merchant, J. T. Edwards,
L. R. Malins, Z. Liu, G. Che, Z. Shen, S. A. Shaw,
M. D. Eastgate and P. S. Baran, Angew. Chem., Int. Ed.,
2017, 56, 11906–11910; Angew. Chem., 2017, 129, 12068–
12072; (g) S. Ni, A. F. Garrido-Castro, R. R. Merchant,
J. N. de Gruyter, D. C. Schmitt, J. J. Mousseau,
G. M. Gallego, S. Yang, M. R. Collins, J. X. Qiao,
K.-S. Yeung, D. R. Langley, M. A. Poss, P. M. Scola, T. Qin
and P. S. Baran, Angew. Chem., Int. Ed., 2018, 57, 14560–
14565; Angew. Chem., 2018, 130, 14768–14773; (h)
T.-G. Chen, H. Zhang, P. K. Mykhailiuk, R. R. Merchant,
C. A. Smith, T. Qin and P. S. Baran, Angew. Chem., Int. Ed.,
2019, 58, 2454–2458; Angew. Chem., 2019, 131, 2476–2480;
(i) F. Sandfort, M. J. O'Neill, J. Cornella, L. Wimmer and
P. S. Baran, Angew. Chem., Int. Ed., 2017, 56, 3319–3323;
Angew. Chem., 2017, 129, 3367–3371; (j) J. Wang, T. Qin,
T.-G. Chen, L. Wimmer, J. T. Edwards, J. Cornella,
B. Vokits, S. A. Shaw and P. S. Baran, Angew. Chem., Int.
Ed., 2016, 55, 9676–9679; Angew. Chem., 2016, 128, 9828–
9831; (k) R. Mao, J. Balon and X. Hu, Angew. Chem., Int.
Ed., 2018, 57, 13624–13628; Angew. Chem., 2018, 130,
13812–13816; (l) J. Cornella, J. T. Edwards, T. Qin,
S. Kawamura, J. Wang, C.-M. Pan, R. Gianatassio,
M. Schmidt, M. D. Eastgate and P. S. Baran, J. Am. Chem.
Soc., 2016, 138, 2174–2177; (m) K. M. M. Huihui,
J. A. Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak,
K. A. Johnson, T. A. DiBenedetto, S. Kim,
L. K. G. Ackerman and D. J. Weix, J. Am. Chem. Soc., 2016,
138, 5016–5019; (n) F. Toriyama, J. Cornella, L. Wimmer,
T.-G. Chen, D. D. Dixon, G. Creech and P. S. Baran, J. Am.
Chem. Soc., 2016, 138, 11132–11135; (o) L. Candish,
M. Teders and F. Glorius, J. Am. Chem. Soc., 2017, 139,
7440–7443; (p) C. Kingston, M. A. Wallace, A. J. Allentoff,
J. N. deGruyter, J. S. Chen, S. X. Gong, S. Bonacorsi and
P. S. Baran, J. Am. Chem. Soc., 2019, 141, 774–779; (q) S. Ni,
N. M. Padial, C. Kingston, J. C. Vantourout, D. C. Schmitt,
J. T. Edwards, M. M. Kruszyk, R. R. Merchant,
P. K. Mykhailiuk, B. B. Sanchez, S. Yang, M. A. Perry,
G. M. Gallego, J. J. Mousseau, M. R. Collins, R. J. Cherney,
9 (a) X.-Y. Yu, Q.-Q. Zhao, J. Chen, J.-R. Chen and W.-J. Xiao,
Angew. Chem., Int. Ed., 2018, 57, 15505–15509; Angew.
Chem., 2018, 130, 15731–15735; (b) M. Claros,
F. Ungeheuer, F. Franco, V. Martin-Diaconescu, A. Casitas
and J. Lloret-Fillol, Angew. Chem., Int. Ed., 2019, 58, 4869–
4874; Angew. Chem., 2019, 131, 4923–4928; (c) S. Guo,
D. I. AbuSalim and S. P. Cook, Angew. Chem., Int. Ed., 2019,
58, 11704–11708; Angew. Chem., 2019, 131, 11830–11834;
(d) Q.-Y. Meng, X.-W. Gao, T. Lei, Z. Liu, F. Zhan, Z.-J. Li,
J.-J. Zhong, H. Xiao, K. Feng, B. Chen, Y. Tao, C.-H. Tung
and L.-Z. Wu, Sci. Adv., 2017, 3, e1700666; (e) Z. Liu,
H. Chen, Y. Lv, X. Tan, H. Shen, H.-Z. Yu and C. Li, J. Am.
Chem. Soc., 2018, 140, 6169–6175; (f) Y. Li, K. Zhou,
Z. Wen, S. Cao, X. Shen, M. Lei and L. Gong, J. Am. Chem.
Soc., 2018, 140, 15850–15858.
10 (a) S. E. Creutz, K. J. Lotito, G. C. Fu and J. C. Peters, Science,
2012, 338, 647–651; (b) Q. M. Kainz, C. D. Matier,
A. Bartoszewicz, S. L. Zultanski, J. C. Peters and G. C. Fu,
Science, 2016, 351, 681–684; (c) W. Zhao, R. P. Wurz,
J. C. Peters and G. C. Fu, J. Am. Chem. Soc., 2017, 139,
12153–12156; (d) C. D. Matier, J. Schwaben, J. C. Peters
and G. C. Fu, J. Am. Chem. Soc., 2017, 139, 17707–17710; (e)
J. M. Ahn, J. C. Peters and G. C. Fu, J. Am. Chem. Soc.,
2017, 139, 18101–18106.
11 (a) D. B. Bagal, G. Kachkovskyi, M. Knorn, T. Rawner,
B. M. Bhanage and O. Reiser, Angew. Chem., Int. Ed., 2015,
54, 6999–7002; Angew. Chem., 2015, 127, 7105–7108; (b)
A. Hossain, A. Vidyasagar, C. Eichinger, C. Lankes, J. Phan,
J. Rehbein and O. Reiser, Angew. Chem., Int. Ed., 2018, 57,
8288–8292; Angew. Chem., 2018, 130, 8420–8424.
12 (a) A. Sagadevan and K. C. Hwang, Adv. Synth. Catal., 2012,
354, 3421–3427; (b) A. Sagadevan, A. Ragupathi and
K. C. Hwang, Angew. Chem., Int. Ed., 2015, 54, 13896–
13901; Angew. Chem., 2015, 127, 14102–14107; (c)
A. Sagadevan, V. P. Charpe, A. Ragupathi and K. C. Hwang,
J. Am. Chem. Soc., 2017, 139, 2896–2899; (d) A. Sagadevan,
A. Ragupathi, C.-C. Lin, J. R. Hwu and K. C. Hwang, Green
Chem., 2015, 17, 1113–1119; (e) V. P. Charpe, A. A. Hande,
A. Sagadevan and K. C. Hwang, Green Chem., 2018, 20,
4859–4864.
13 A. Hazra, M. T. Lee, J. F. Chiu and G. Lalic, Angew. Chem., Int.
Ed., 2018, 57, 5492–5496; Angew. Chem., 2018, 130, 5590–
5594.
14 (a) Q.-Q. Zhou, W. Guo, W. Ding, X. Wu, X. Chen, L.-Q. Lu
and W.-J. Xiao, Angew. Chem., Int. Ed., 2015, 54, 11196–
11199; Angew. Chem., 2015, 127, 11348–11351; (b) F. Le
Vaillant, T. Courant and J. Waser, Angew. Chem., Int. Ed.,
2015, 54, 11200–11204; Angew. Chem., 2015, 127, 11352–
11356; (c) H.-P. Bi, L. Zhao, Y.-M. Liang and C.-J. Li, Angew.
Chem., Int. Ed., 2009, 48, 792–795; Angew. Chem., 2009,
121, 806–809; (d) C. Zhang and D. Seidel, J. Am. Chem. Soc.,
2010, 132, 1798–1799; (e) Y.-S. Feng, Z.-Q. Xu, L. Mao,
Chem. Sci.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
P. S. Lebed, J. S. Chen, T. Qin and P. S. Baran, J. Am. Chem. 19 (a) C. Le, T. Q. Chen, T. Liang, P. Zhang and
Soc., 2019, 141, 6726–6739; (r) H. Li, C. P. Breen, H. Seo,
T. F. Jamison, Y.-Q. Fang and M. M. Bio, Org. Lett., 2018,
20, 1338–1341; (s) H. Zhang, P. Zhang, M. Jiang, H. Yang
and H. Fu, Org. Lett., 2017, 19, 1016–1019; (t) J. Yang,
D. W. C. MacMillan, Science, 2018, 360, 1010–1014; (b)
A. Tlahuext-Aca, L. Candish, R. A. Garza-Sanchez and
F. Glorius, ACS Catal., 2018, 8, 1715–1719; (c) Y. Ye and
M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034–9037.
J. Zhang, L. Qi, C. Hu and Y. Chen, Chem. Commun., 2015, 20 F. D. Lu, D. Liu, L. Zhu, L. Q. Lu, Q. Yang, Q. Q. Zhou, Y. Wei,
51, 5275–5278; (u) C. R. Jamison and L. E. Overman, Acc.
Chem. Res., 2016, 49, 1578–1586.
Y. Lan and W. J. Xiao, J. Am. Chem. Soc., 2019, 141, 6167–
6172.
16 For computational details, see the ESI.‡
21 J. Jover, J. Chem., 2015, 2015, 1–8.
17 P. Xiao, C. X. Li, W. H. Fang, G. Cui and W. Thiel, J. Am. 22 (a) P. Leophairatana, S. Samanta, C. C. De Silva and
Chem. Soc., 2018, 140, 15099–15113.
18 J. W. Hilborn and J. A. Pincock, J. Am. Chem. Soc., 1991, 113,
2683–2686.
J. T. Koberstein, J. Am. Chem. Soc., 2017, 139, 3756; (b)
D. K. Das, V. K. Kumar Pampana and K. C. Hwang, Chem.
Sci., 2018, 9, 7318.
This journal is © The Royal Society of Chemistry 2020
Chem. Sci.