Regio- And Stereoselective Synthesis of Diverse 3,4-Dihydro-2-quinolones through Catalytic Hydrative Cyclization of Imine- And Carbonyl-Ynamides with Water

Article abstract of DOI:10.1021/acscatal.0c04786

Transition-metal-catalyzed alkyne hydration reaction has attracted considerable interest in the past decades because this approach would lead to the facile and efficient formation of synthetically useful carbonyls. However, transition-metal-catalyzed alky

Full text of DOI:10.1021/acscatal.0c04786

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Regio- and Stereoselective Synthesis of Diverse 3,4-Dihydro-2-
quinolones through Catalytic Hydrative Cyclization of Imine- and
Carbonyl-Ynamides with Water
Bo-Han Zhu,# Ying-Qi Zhang,# Hao-Jin Xu, Long Li, Guo-Cheng Deng, Peng-Cheng Qian,*
Chao Deng,* and Long-Wu Ye*
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ABSTRACT: Transition-metal-catalyzed alkyne hydration reac-
tion has attracted considerable interest in the past decades because
this approach would lead to the facile and efficient formation of
synthetically useful carbonyls. However, transition-metal-catalyzed
alkyne hydration-initiated tandem reactions have seldom been
explored because their metal enolate intermediates generally
undergo facile protodemetallation rather than further trapped by
other types of electrophiles. Described herein is an efficient copper-
catalyzed tandem alkyne hydration/intramolecular Mannich
reaction of imine-ynamides with water. This method allows
efficient and diastereodivergent synthesis of valuable 3,4-dihydro-2-quinolones with high regio-, diastereo-, and enantioselectivity.
Moreover, this hydrative cyclization can also be applicable to the hydrative aldol reaction of carbonyl-ynamides with water to form
3,4-dihydro-2-quinolones regio- and diastereoselectively by employing zinc as the catalyst.
KEYWORDS: cyclization, cascade, heterocycles, alkynes, stereoselectivity
Scheme 1. (a, b) Transition-Metal-Catalyzed Hydrative
Aldol and Mannich Reactions of Alkynes
INTRODUCTION
■
Transition-metal-catalyzed alkyne hydration reaction (M = Au,
Pt, Pd, Ag, Zn, and Hg) has attracted considerable interest in
the past decades because this approach would lead to the facile
and efficient formation of synthetically useful carbonyl
derivatives from the readily available alkynyl substrates.1,2 In
particular, a high turnover frequency (TOF) has been achieved
in the gold-catalyzed reaction system,3 as elegantly established
by Hayashi et al.,3a Nolan et al.,3b Zhang et al.,3c and Zuccaccia
et al.3d Despite these significant achievements, transition-
metal-catalyzed alkyne hydration-initiated tandem reactions
have seldom been explored due to the fact that their metal
enolate intermediates generally undergo facile protodemetalla-
tion rather than further trapped by other types of electrophiles
such as carbonyls and imines.4−6 A major breakthrough was
the zinc-catalyzed hydrative aldol reaction of 3-en-1-ynamides
with aldehydes and water developed by Liu and co-workers in
2015 (Scheme 1a).5a Subsequently, the relevant gold-catalyzed
tandem imination/Mannich reaction of enynamide with
anilines and aldehydes was realized by the same group.5b
Notable is that the conjugated enynes are generally required
for these reactions, and the poor diastereoselectivity was
obtained in the case of typical internal ynamides. Very recently,
Shi et al. disclosed an elegant formal tandem alkyne hydration/
aldol addition via Au−Fe dual catalysis, but this protocol relies
on the carbonyl-group neighboring-group participation.6a
Received: November 4, 2020
Revised: January 2, 2021
Published: January 20, 2021
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© 2021 American Chemical Society
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Therefore, the development of novel alkyne hydration-initiated
tandem reactions, especially those with high flexibility,
efficiency, and stereoselectivity, is highly desirable.
aldol reaction of carbonyl-ynamides with water to form 3,4-
dihydro-2-quinolones regio- and diastereoselectively by
employing zinc as the catalyst. In this article, we report the
results of our detailed investigations on this type of catalytic
hydrative Mannich and aldol reactions, including substrate
scopes, synthetic applications, and mechanistic studies.
Inspired by the above achievements and by our recent work
on developing ynamide chemistry for N-heterocycle syn-
thesis,7,8 we envisioned that the catalytic intramolecular
hydrative Mannich reaction of imine-ynamides with water
might be feasible, thus leading to the formation of the
corresponding 3,4-dihydro-2-quinolones (Scheme 1b), which
exist in a range of bioactive molecules and natural products
(Figure 1).9 However, realizing this hydrative cyclization,
RESULTS AND DISCUSSION
■
At the outset, the tert-butylsulfonyl (Bus)-substituted imine-
ynamide 1a10 was chosen as the model substrate due to the
facile removal of the Bus group of the formed products.11
Table 1 shows the realization of the hydrative cyclization
reaction of imine-ynamide 1a with water in the presence of
various transition-metal catalysts.12 The reaction was first
performed under Liu’s group previously developed condition-
s,5a and the desired hydrative cyclization product 2a could be
obtained in 45% yield together with significant formation of
hydration product 2ab (entry 1). Further screening of other
Lewis acids such as Sc(OTf)3 and Y(OTf)3 only led to the
decomposition of substrate 1a (entries 2−5). To our delight,
product 2a was formed in 60% yield in the presence of CuOTf
albeit still with significant amounts of hydration product 2aa
(entry 6). In addition, the use of other copper catalysts such as
Cu(OTf)2 and Cu(CH3CN)4PF6 failed to improve the
reaction (entries 7 and 8, respectively). Gratifyingly,
subsequent investigations on the reaction concentration
demonstrated that low concentrations were necessary to
circumvent the competing hydration reaction and other side
reactions (entries 9 and 10). The reaction proceeded smoothly
under the concentration of 0.0125 M, affording the desired 3,4-
dihydro-2-quinolone 2a in 88% yield with high diastereose-
lectivity (12:1, entry 10). Of note, the reaction could produce
the desired 2a in the presence of gold catalysts such as
Ph3PAuNTf2 and IPrAuNTf2 and Brønsted acids such as
MsOH and HNTf2 but with low efficiency (<40%).12 In the
absence of the catalyst, the reaction failed to give even a trace
of 2a.
Figure 1. 2-Quinolones in bioactive molecules and natural products.
especially with high regio- and stereoselectivity, is highly
challenging. First, the generated metal enolates may suffer from
the ready protodemetallation process. Second, the imine
moiety may undergo facile hydration before or after the
alkyne hydration to form the carbonyl moiety. Herein, we
describe the realization of such a copper-catalyzed hydrative
Mannich reaction of imine-ynamides with water, which
represents the first catalytic hydrative Mannich reaction. This
method allows efficient, practical, and diastereodivergent
synthesis of valuable 3,4-dihydro-2-quinolones with high
regio-, diastereo-, and enantioselectivity. Furthermore, this
hydrative cyclization can also be applicable to the hydrative
a
Table 1. Optimization of Reaction Conditions
yield (%)
entry
metal catalyst
conditions
d.r.
8:1
2a
2aa
2ab
1
2
3
4
5
6
7
8
9
Zn(OTf)2
Sc(OTf)3
Y(OTf)3
Fe(OTf)3
Fe(OTf)2
CuOTf
Cu(OTf)2
Cu(CH3CN)4PF6
CuOTf
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
CH3CN, 80 °C, 2 h
45
<3
<3
<3
<3
60
16
38
81
88
<3
<3
<3
<3
<3
11
<5
7
16
<3
<3
<3
<3
<3
<5
<3
<3
<3
10:1
6:1
12:1
12:1
CH3CN (0.025 M), 80 °C, 10 h
CH3CN (0.0125 M), 80 °C, 12 h
9
<5
10
CuOTf
a
Reaction conditions: 1a (0.1 mmol), catalyst (0.02 mmol), H2O (0.2 mmol), CH3CN (2 mL), 80 °C, 2−12 h, and in Schlenk tubes; yields are
measured by 1H NMR using diethyl phthalate as the internal standard; and d.r. values are determined by crude 1H NMR. Bus = tert-butylsulfonyl.
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Having the optimum reaction conditions in hand (Table 1,
entry 10), the reaction scope of the copper-catalyzed hydrative
cyclization of Bus-substituted imine-ynamides with water was
then explored. As shown in Table 2, the reaction proceeded
in all cases. The relative configuration of 2m was confirmed by
X-ray diffraction analysis (Figure 2).13 Thereby, this protocol
Table 2. Reaction Scope for the Hydrative Cyclization of
a
Imine-Ynamides 1
Figure 2. Structure of compound 2m in its crystal.
not only represents the first catalytic hydrative Mannich
reaction but also provides a highly efficient and practical route
to prepare valuable structurally diverse 3,4-dihydro-2-quino-
lones.14
Although our attempts to employ various chiral ligands such
as bisoxazoline (BOX) ligands and biphosphine ligands to
realize this asymmetric catalysis failed, the asymmetric
hydrative Mannich reaction could be achieved by combination
of chiral tert-butylsulfinimine chemistry.15 As depicted in Table
3, the treatment of (S)-tert-butylsulfinimine-substituted imine-
ynamides 3 with 2 equiv of H2O in the presence of CuOTf
allowed the enantioselective synthesis of the corresponding
Table 3. Reaction Scope for the Hydrative Cyclization of
a
Chiral Imine-Ynamides 3
a
Reactions run in vials; 1 (0.2 mmol), CuOTf (0.04 mmol), H2O (0.4
mmol), CH3CN (16 mL), 80 °C, 12 h, and in Schlenk tubes; yields
are those for the isolated products; and d.r. values are determined by
b
1
crude H NMR. Using 20 mol % Cu(CH3CN)4PF6 as the catalyst.
PG = protecting group. Bs = 4-bromobenzenesulfonyl.
smoothly with a range of aryl-tethered imine-ynamides 1, and
the corresponding 3,4-dihydro-2-quinolones 2 were obtained
in generally high yields. In addition to the Ts group, ynamide
containing a Bs group was also a suitable substrate for this
hydrative cyclization to furnish the desired benzo-fused δ-
lactam 2b in 79% yield. In addition, the reaction occurred
efficiently for various aryl-substituted ynamides (R1 = Ar) and
ynamides bearing both electron-withdrawing and electron-
donating groups, producing the corresponding δ-lactams 2c−
2p in mostly good yields. This chemistry could also be
extended to alkyl- and allyl-substituted ynamides to afford the
desired products 2q−2s in 64−79% yields. Interestingly,
substrates with the Ts-substituted imine moiety could also
be readily converted into the expected 3,4-dihydro-2-
quinolones 2t and 2u in good yields. Attempts to synthesize
the gem-disubstituted imine-ynamides and alkyl-tethered
imine-ynamides failed probably due to the fact that these
imine-ynamides are extremely unstable. Finally, it is notable
that the unique regioselectivity here is distinctively different
from the related copper-catalyzed arylative cyclization of
imine-ynamides with arylboronic acids,10 where regioselective
nucleophilic addition on the β-position of ynamides was
observed. Importantly, high diastereoselectivity was achieved
a
Reactions run in vials; 3 (0.2 mmol), CuOTf (0.04 mmol), H2O (0.4
mmol), CH3CN (32 mL), 60 °C, 6 h, and in Schlenk tubes; yields are
those for the isolated products; d.r. values are determined by crude 1H
b
NMR; and ee values are determined by HPLC analysis. (R)-tert-
Butylsulfinamide-derived 3a′ was used as the substrate.
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chiral 3,4-dihydro-2-quinolones 4a−4j in respectable yields. Of
note, the reaction of alkyl-substituted imine-ynamide could
also afford the desired product 4j in 54% yield albeit with poor
diastereoselectivity. In addition, the (R)-(+)-tert-butylsulfina-
mide-derived 3a′ also underwent smooth cyclization to
specifically produce the other enantiomer 4a′ in 58% yield.
To our surprise, divergent diastereoselectivity (trans-cycliza-
tion) was observed in this protocol. Importantly, unique
regioselectivity, generally high diastereoselectivity, and ex-
cellent enantioselectivity were achieved in these cases. The
absolute configurations of 4g and 4a′ were established based
on X-ray crystallographic analysis (Figure 3).13
substrates for this reaction, leading to the corresponding
benzo-δ-lactams 6a−6c in 84−87% yields with high diaster-
eoselectivity, respectively. The reaction occurred smoothly
with different aryl-substituted ynamides (R1 = Ar), delivering
the desired δ-lactams 6d−6h in good to excellent yields. The
method also proceeded efficiently for various aryl-tethered
ynamides bearing both electron-withdrawing and electron-
donating groups, and the expected products 6i−6m were
formed in 95−97% yields. Additionally, alkyl-substituted
ynamides were also feasible for this hydrative cyclization to
afford the desired 6n−6o in 91−92% yields. In addition to
aldehyde-ynamides, ketone-ynamides 5p−5s also reacted
smoothly to produce the corresponding 3,4-dihydro-2-
quinolones 6p−6s in 77−95% yields, respectively.16 Interest-
ingly, the reaction could be extended to terminal ynamides to
deliver the desired 6r and 6s efficiently. Finally, it is worth
noting that the use of the alkyl-tethered aldehyde-ynamides
also led to the expected δ-lactams 6t and 6u in good yields, but
low diastereoselectivity was obtained in the case of the alkyl-
substituted ynamide (R1 = alkyl). Thus, the hydrative aldol
reaction exhibits a broader substrate scope in comparison with
the above hydrative Mannich reaction. The relative config-
uration of 6l was confirmed by X-ray diffraction analysis
(Figure 4).13
Figure 3. Structures of compounds 4g and 4a′ in their crystals.
In addition, this hydrative cyclization is applicable to
carbonyl-ynamides 5 catalyzed by zinc,12 affording the
corresponding 3,4-dihydro-2-quinolones 6 in generally good
to excellent yields with unique regioselectivity and generally
high diastereoselectivity (Table 4). Ynamides with different N-
protecting groups were first investigated, and it was found that
Ts-, Bs-, and Ms-substituted ynamides were all suitable
Figure 4. Structure of compound 6l in its crystal.
Table 4. Reaction Scope for the Hydrative Cyclization of
Carbonyl-Ynamides 5
a
In addition to ynamides, this zinc-catalyzed cascade
cyclization also occurred efficiently with alkynyl ethers 7,
thus affording the desired dihydrocoumarins 8a and 8b in good
yields (eq 1).17 Of note, this heterocyclic moiety can also be
found in a variety of bioactive natural and non-natural
products.9a,18
Further synthetic applications of the as-synthesized 3,4-
dihydro-2-quinolones were then explored. For example, the
Bus group in 2a, obtained on a gram scale in 85% yield by
employing 10 mol % CuOTf as the catalyst, was smoothly
removed upon treatment with AlCl3 (Scheme 2a).19 The free
amine was capped with a Cbz or Boc group to facilitate
isolation of the product. The preparative-scale reaction of 3a
was also performed in the presence of 5 mol % CuOTf as the
catalyst, affording 4a in 58% yield and 99% ee. 4a could
undergo subsequent m-CPBA oxidation and replacement of
the Bus group with the Cbz group, leading to 4ab in 38% yield
(three steps) with well-maintained enantioselectivity (Scheme
2b). Of note, attempts to remove the sulfoxide group of 4a
under various conditions only resulted in the formation of 2-
quinolone 6aa via β-elimination. Moreover, the formal
synthesis of natural product ( )-martinellic acid was achieved
a
Reaction conditions: 5 (0.2 mmol), Zn(OTf)2 (0.04 mmol), H2O
(0.4 mmol), toluene/CH3CN (3 mL/1 mL), 80 °C, 2 h, and in
Schlenk tubes; yields are those for the isolated products; and d.r.
b
values are determined by crude 1H NMR. Using 20 mol % Y(OTf)3
c
as the catalyst. Using CH3CN as the solvent, 60 °C, and 5 h.
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2d). Interestingly, the synthesis of the anticancer agent 6vb9e
could also be achieved by starting from the corresponding
ynamide 5v through tandem hydrative cyclization/dehydration
by simply extending the reaction time and subsequent
deprotection (Scheme 2d).
Scheme 2. (a−d) Gram- or Preparative-Scale Reactions and
Synthetic Applications
To probe the reaction mechanism, we first subjected 2aa to
the optimal reaction conditions and found that the reaction
only afforded the corresponding 2ab in 20% yield (75% 2aa
recovered) and the formation of 2a was not observed, thus
ruling out 2aa as an intermediate for the formation of 2a (eq
2). In addition, when the reaction was run in the presence of
10 equiv of D2O, 62% deuterium incorporation at the α-
position of amide was detected (eq 3). As shown in eq 4, we
also performed the reaction in the presence of 10 equiv of
H218O and found that an oxygen atom was incorporated into
the product (18O incorporation: >80%). These results suggest
that the oxygen of the newly formed carbonyl group of product
2a originates from the water.
On the basis of the above experimental observations, density
functional theory (DFT) calculations, and previous works,5,6
plausible reaction mechanisms for stereoselective synthesis of
3,4-dihydro-2-quinolones 2a, 4a, and 6a were proposed, as
shown in Scheme 3. The reaction presumably involves the
formation of Z/E-configured metal enolate intermediates
followed by intramolecular cyclization by the Mannich reaction
and aldol reaction, respectively, via preferred chair-like
transition states. Through the DFT calculations, it is found
that the activation barriers of cis-2a and cis-6a are lower than
trans-2a and trans-6a by 15.1 and 9.5 kcal/mol, respectively. In
the case of sulfoxide ynamide 3a, the positive charge can be
located on the low-valent sulfur atom with the proton linked
with the oxygen atom of the sulfoxide moiety. According to
this catalytic model, the barrier of trans-4a is 1.5 kcal/mol
lower than cis-4a. Thus, the sulfoxide moiety of 3a not only
dominates the observed high enantioselectivity but also leads
to the divergent diastereoselectivity. Moreover, the free
energies of cis-2a, cis-6a, and trans-4a are more stable than
trans-2a, trans-6a, and cis-4a by 3.7, 1.2, and 3.0 kcal/mol,
respectively.12,21 Hence, these computational results are
consistent with the experimental observations in the cyclization
reactions.
by this method (Scheme 2c). Oxidation of the alkenyl group of
2u with RuCl3 and NaIO4 led to the formation of aza-
hemiacetal 2ua in 68% yield, which was further transformed
into the desired 2uc in 40% yield (three steps) upon selective
reduction of the hydroxyl group by silane and reduction of the
amide group by DIBAL-H followed by allylation. Subsequent
deprotection of both tosyl groups and selective N-Bn
protection of the pyrrolidine moiety allowed the formation
of the final product 2ud, which has been previously converted
into natural product ( )-martinellic acid.20 In addition, 6aa,
obtained in 86% yield through the standard hydrative
cyclization and dehydration in a one-pot process, could be
further converted into 6ab as a KGFR inhibitor9f and 6ac as a
KGFR inhibitor9f and an antitumor agent9h via deprotection of
the tosyl group8g and simultaneous deprotection of the tosyl
group and reduction of the double bond, respectively (Scheme
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Scheme 3. Plausible Reaction Mechanism and Theoretical
Studies on the Key Transition States for the cis and trans
Selectivity in the Hydrative Cyclization of Ynamides 1a, 3a,
and 5a. The Relative Free Energies Are Given in kcal/mol
Crystallographic data of 4g (CIF)
Crystallographic data of 4a′ (CIF)
Crystallographic data of 6l (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
Peng-Cheng Qian − Institute of New Materials & Industry
Technology, College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, China;
Email: qpc@wzu.edu.cn
Chao Deng − Jiangsu Key Laboratory of Pesticide Science and
Department of Chemistry, College of Sciences, Nanjing
Agricultural University, Nanjing 210095, China;
orcid.org/0000-0002-0899-3305; Email: chaodeng@
njau.edu.cn
Long-Wu Ye − Key Laboratory for Chemical Biology of Fujian
Province, State Key Laboratory of Physical Chemistry of Solid
Surfaces, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China;
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0003-3108-
2611; Email: longwuye@xmu.edu.cn
Authors
Bo-Han Zhu − Key Laboratory for Chemical Biology of Fujian
Province, State Key Laboratory of Physical Chemistry of Solid
Surfaces, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
Ying-Qi Zhang − Key Laboratory for Chemical Biology of
Fujian Province, State Key Laboratory of Physical Chemistry
of Solid Surfaces, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
Hao-Jin Xu − Key Laboratory for Chemical Biology of Fujian
Province, State Key Laboratory of Physical Chemistry of Solid
Surfaces, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
Long Li − Institute of New Materials & Industry Technology,
College of Chemistry & Materials Engineering, Wenzhou
University, Wenzhou 325035, China
CONCLUSIONS
■
In summary, we have developed the challenging tandem alkyne
hydration/intramolecular Mannich reaction of imine-ynamides
with water by copper catalysis, which represents the first
example of the catalytic hydrative Mannich reaction. Moreover,
such an asymmetric hydrative cyclization has been achieved
with divergent diastereoselectivity and high enantioselectivities
(up to 99% ee) by combination of chiral tert-butylsulfinimine
chemistry. In addition, this cascade cyclization can also be
applicable to the zinc-catalyzed hydrative aldol reaction of
carbonyl-ynamides with water. These cascade cyclizations
deliver structurally diverse 3,4-dihydro-2-quinolones with
unique regioselectivity and high stereoselectivity. The synthetic
utility of this chemistry is indicated by the practical and
efficient synthesis of two bioactive compounds and formal
synthesis of natural product ( )-martinellic acid. Thus, this
method opens novel and concise routes to valuable 3,4-
dihydro-2-quinolone derivatives. Theoretical calculations are
also performed to clarify the origins of diastereoselectivity and
enantioselectivity. Owing to these advantages, we believe that
this chemistry will be welcomed by academic and industrial
researchers. Further direction will focus on the development of
the asymmetric version of this protocol by chiral Lewis acid
catalysis.
Guo-Cheng Deng − Key Laboratory for Chemical Biology of
Fujian Province, State Key Laboratory of Physical Chemistry
of Solid Surfaces, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04786
Author Contributions
#B.-H.Z. and Y.-Q.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21772161, 21622204, and
21828102), the Natural Science Foundation of Fujian Province
of China (2019J02001), the President Research Funds from
Xiamen University (20720180036), the Fundamental Research
Funds for the Central Universities (20720202008), NFFTBS
(J1310024), PCSIRT, the Science & Technology Cooperation
Program of Xiamen (3502Z20183015), the Opening Project of
PCOSS, Xiamen University (201909), the Bioinformatics
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04786.
■
sı
Experimental procedures, compound characterization
data, computational details, and NMR and HPLC
spectra (PDF)
Crystallographic data of 2m (CIF)
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(4) Only few gold enolates generated in alkyne hydrations were
functionalized with arylations or fluorination, see: (a) Wang, W.;
Jasinski, J.; Hammond, G. B.; Xu, B. Fluorine-Enabled Cationic Gold
Catalysis: Functionalized Hydration of Alkynes. Angew. Chem., Int. Ed.
Engl. 2010, 49, 7247−7252. (b) de Haro, T.; Nevado, C. Gold-
Catalyzed Synthesis of α-Fluoro Acetals and α-Fluoro Ketones from
Alkynes. Adv. Synth. Catal. 2010, 352, 2767−2772. For other
representative examples, see: (c) Ouyang, X.-H.; Tan, F.-L.; Song, R.-
J.; Deng, W.; Li, J.-H. Palladium-Catalyzed Oxidative [2 + 2 + 1]
Annulation of 1,7-Diynes with H2O: Entry to Furo[3,4-c]quinolin-
4(5H)-ones. Org. Lett. 2018, 20, 6765−6768. (d) Chen, Y.; Park, S.
H.; Lee, C. W.; Lee, C. Ruthenium-Catalyzed Three-Component
Coupling via Hydrative Conjugate Addition of Alkynes to Alkenes:
One-Pot Synthesis of 1,4-Dicarbonyl Compounds. Chem. − Asian J.
2011, 6, 2000−2004. (e) Zhang, C.; Cui, D.-M.; Yao, L.-Y.; Wang, B.-
S.; Hu, Y.-Z.; Hayashi, T. Synthesis of 2-Cyclohexenone Derivatives
via Gold(I)-Catalyzed Hydrative Cyclization of 1,6-Diynes. J. Org.
Chem. 2008, 73, 7811−7813.
(5) (a) Jadhav, A. M.; Pagar, V. V.; Huple, D. B.; Liu, R. S. Zinc(II)-
Catalyzed Intermolecular Hydrative Aldol Reactions of 2-En-1-
ynamides with Aldehydes and Water to form Branched Aldol
Products Regio- and Stereoselectively. Angew. Chem., Int. Ed. 2015,
54, 3812−3816. (b) Singh, R. R.; Liu, R. S. Gold-Catalyzed
Imination/Mannich Reaction Cascades of 3-En-1-ynamides with
Anilines and Aldehydes to Enable 1,5-Nitrogen Functionalizations.
Adv. Synth. Catal. 2016, 358, 1421−1427.
(6) For an elegant formal tandem alkyne hydration/aldol addition
enabled by carbonyl-group neighboring-group participation via Au−
Fe dual catalysis, see: (a) Yuan, T.; Ye, X.; Zhao, P.; Teng, S.; Yi, Y.;
Wang, J.; Shan, C.; Wojtas, L.; Jean, J.; Chen, H.; Shi, X.
Regioselective Crossed Aldol Reactions under Mild Conditions via
Synergistic Gold-Iron Catalysis. Chem. 2020, 6, 1420−1431. For a
formal intramolecular hydrative cyclization involving the copper and
acetic acid comediated hydration of terminal alkynes followed by the
pyrrolidine-mediated aldol reaction, see: (b) He, G.; Wu, C.; Zhou, J.;
Yang, Q.; Zhang, C.; Zhou, Y.; Zhang, H.; Liu, H. A Method for
Synthesis of 3-Hydroxy-1-indanones via Cu-Catalyzed Intramolecular
Annulation Reactions. J. Org. Chem. 2018, 83, 13356−13362.
(7) For recent reviews on ynamide reactivity, see: (a) Lynch, C. C.;
Sripada, A.; Wolf, C. Asymmetric Synthesis with Ynamides: Unique
Reaction Control, Chemical Diversity and Applications. Chem. Soc.
Rev. 2020, 49, 8543. (b) Chen, Y.-B.; Qian, P.-C.; Ye, L.-W. Brønsted
Acid-Mediated Reactions of Ynamides. Chem. Soc. Rev. 2020, 49,
8897. (c) Hong, F.-L.; Ye, L.-W. Transition Metal-Catalyzed Tandem
Reactions of Ynamides for Divergent N-Heterocycle Synthesis. Acc.
Chem. Res. 2020, 53, 2003−2019. (d) Zhou, B.; Tan, T.-D.; Zhu, X.-
Q.; Shang, M.; Ye, L.-W. Reversal of Regioselectivity in Ynamide
Chemistry. ACS Catal. 2019, 9, 6393−6406. (e) Evano, G.;
Theunissen, C.; Lecomte, M. Ynamides: powerful and versatile
reagents for chemical synthesis. Aldrichimica Acta 2015, 48, 59−77.
(f) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.;
Kedrowski, B. L.; Hsung, R. P. Ynamides in Ring Forming
Transformations. Acc. Chem. Res. 2014, 47, 560−578. (g) DeKorver,
K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R.
P. Ynamides: A Modern Functional Group for the New Millennium.
Chem. Rev. 2010, 110, 5064−5106. (h) Evano, G.; Coste, A.; Jouvin,
K. Ynamides: Versatile Tools in Organic Synthesis. Angew. Chem., Int.
Ed. 2010, 49, 2840−2859.
Center of Nanjing Agricultural University, and the Start-up
Research Fund of Nanjing Agricultural University (050-
804099). We also thank Mr. Zanbin Wei from Xiamen
University for assistance with X-ray crystallographic analysis.
REFERENCES
■
(1) For recent selected reviews, see: (a) Brenzovich, W. E., Jr. Gold
in Total Synthesis: Alkynes as Carbonyl Surrogates. Angew. Chem., Int.
Ed. 2012, 51, 8933−8935. (b) Hintermann, L.; Labonne, A. Catalytic
Hydration of Alkynes and Its Application in Synthesis. Synthesis 2007,
2007, 1121−1150.
(2) For selected examples, see: (a) Jadhav, A. M.; Gawade, S. A.;
Vasu, D.; Dateer, R. B.; Liu, R. S. ZnII- and AuI-Catalyzed
Regioselective Hydrative Oxidations of 3-En-1-ynes with Selectfluor:
Realization of 1,4-Dioxo and 1,4-Oxohydroxy Functionalizations.
Chem. - Eur. J. 2014, 20, 1813−1817. (b) Tachinami, T.; Nishimura,
T.; Ushimaru, R.; Noyori, R.; Naka, H. Hydration of Terminal
Alkynes Catalyzed by Water-Soluble Cobalt Porphyrin Complexes. J.
Am. Chem. Soc. 2013, 135, 50−53. (c) Chen, Z. W.; Ye, D. N.; Qian,
Y. P.; Ye, M.; Liu, L. X. Highly Efficient AgBF4-Catalyzed Synthesis of
Methyl Ketones from Terminal Alkynes. Tetrahedron 2013, 69,
6116−6120. (d) Li, X.; Hu, G.; Luo, P.; Tang, G.; Gao, Y.; Xu, P.;
Zhao, Y. Palladium(II)-Catalyzed Hydration of Alkynylphosphonates
to β-Ketophosphonates. Adv. Synth. Catal. 2012, 354, 2427−2432.
(e) Thuong, M. B. T.; Mann, A.; Wagner, A. Mild Chemo-Selective
Hydration of Terminal Alkynes Catalysed by AgSbF6. Chem. Commun.
2012, 48, 434−436. (f) Lein, M.; Rudolph, M.; Hashmi, S. K.;
Schwerdtfeger, P. Homogeneous Gold Catalysis: Mechanism and
Relativistic Effects of the Addition of Water to Propyne. Organo-
metallics 2010, 29, 2206−2210. (g) Pernpointner, M.; Hashmi, A. S.
K. Fully Relativistic, Comparative Investigation of Gold and Platinum
Alkyne Complexes of Relevance for the Catalysis of Nucleophilic
Additions to Alkynes. J. Chem. Theory Comput. 2009, 5, 2717−2725.
(h) Wu, X. F.; Bezier, D.; Darcel, C. Development of the First Iron
Chloride-Catalyzed Hydration of Terminal Alkynes. Adv. Synth. Catal.
2009, 351, 367−370. (i) Kanemitsu, H.; Uehara, K.; Fukuzumi, S.;
Ogo, S. Isolation and Crystal Structures of Both Enol and Keto
Tautomer Intermediates in a Hydration of an Alkyne-Carboxylic Acid
Ester Catalyzed by Iridium Complexes in Water. J. Am. Chem. Soc.
2008, 130, 17141−17147. (j) Casado, R.; Contel, M.; Laguna, M.;
Romero, P.; Sanz, S. Organometallic Gold(III) Compounds as
Catalysts for the Addition of Water and Methanol to Terminal
Alkynes. J. Am. Chem. Soc. 2003, 125, 11925−11935. (k) Budde, W.
L.; Dessy, R. E. The Homogeneously Catalyzed Hydration of
Acetylenes by Mercuric Perchlorate-Perchloric Acid: Evidence for a
Bis-(acetylene)-Mercuric Ion Complex as an Intermediate. J. Am.
Chem. Soc. 1963, 85, 3964−3970.
(3) For recent examples, see: (a) Mizushima, E.; Sato, K.; Hayashi,
T.; Tanaka, M. Highly Efficient AuI-Catalyzed Hydration of Alkynes.
́
Angew. Chem., Int. Ed. 2002, 41, 4563−4565. (b) Marion, N.; Ramon,
R. S.; Nolan, S. P. [(NHC)AuI]-Catalyzed Acid-Free Alkyne
Hydration at Part-per-Million Catalyst Loadings. J. Am. Chem. Soc.
2009, 131, 448−449. (c) Wang, Y.; Wang, Z.; Li, Y.; Wu, G.; Cao, Z.;
Zhang, L. A General Ligand Design for Gold Catalysis Allowing
Ligand-Directed Anti-Nucleophilic Attack of Alkynes. Nat. Commun.
2014, 5, 3470. (d) Gatto, M.; Belanzoni, P.; Belpassi, L.; Biasiolo, L.;
Del Zotto, A.; Tarantelli, F.; Zuccaccia, D. Solvent-, Silver-, and Acid-
Free NHC-Au-X Catalyzed Hydration of Alkynes. The Pivotal Role of
the Counterion. ACS Catal. 2016, 6, 7363−7376. For the highest
turnover numbers in nucleophilic alcohol additions to alkynes, see:
(e) Jaimes, M. C. B.; Rominger, F.; Pereira, M. M.; Carrilho, R. M. B.;
Carabineiro, S. A. C.; Hashmi, A. S. K. Highly Active Phosphite
Gold(I) Catalysts for Intramolecular Hydroalkoxylation, Enyne
Cyclization and Furanyne Cyclization. Chem. Commun. 2014, 50,
(8) For recent selected examples, see: (a) Hong, F.-L.; Chen, Y.-B.;
Ye, S.-H.; Zhu, G.-Y.; Zhu, X.-Q.; Lu, X.; Liu, R.-S.; Ye, L.-W. Copper-
Catalyzed Asymmetric Reaction of Alkenyl Diynes with Styrenes by
Formal [3 + 2] Cycloaddition via Cu-Containing All-Carbon 1,3-
Dipoles: Access to Chiral Pyrrole-Fused Bridged [2.2.1] Skeletons. J.
Am. Chem. Soc. 2020, 142, 7618−7626. (b) Wang, Z.-S.; Chen, Y.-B.;
Zhang, H.-W.; Sun, Z.; Zhu, C.; Ye, L.-W. Ynamide Smiles
Rearrangement Triggered by Visible-Light-Mediated Regioselective
Ketyl−Ynamide Coupling: Rapid Access to Functionalized Indoles
and Isoquinolines. J. Am. Chem. Soc. 2020, 142, 3636−3644. (c) Liu,
X.; Wang, Z.-S.; Zhai, T.-Y.; Luo, C.; Zhang, Y.-P.; Chen, Y.-B.; Deng,
̈
4937−4940. (f) Jaimes, M. C. B.; Bohling, C. R. N.; Serrano-Becerra,
J. M.; Hashmi, A. S. K. Highly Active Mononuclear NAC−Gold(I)
Catalysts. Angew. Chem., Int. Ed. 2013, 52, 7963−7966.
1712
https://dx.doi.org/10.1021/acscatal.0c04786
ACS Catal. 2021, 11, 1706−1713

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
C.; Liu, R.-S.; Ye, L.-W. Copper-Catalyzed Azide-Ynamide Cyclization
to Generate α-Imino Copper Carbenes: Divergent and Enantiose-
lective Access to Polycyclic N-Heterocycles. Angew. Chem., Int. Ed.
2020, 59, 17984−17990. (d) Hong, F.-L.; Wang, Z.-S.; Wei, D.-D.;
Zhai, T.-Y.; Deng, G.-C.; Lu, X.; Liu, R.-S.; Ye, L.-W. Generation of
Donor/Donor Copper Carbenes through Copper-Catalyzed Diyne
Cyclization: Enantioselective and Divergent Synthesis of Chiral
Polycyclic Pyrroles. J. Am. Chem. Soc. 2019, 141, 16961−16970.
(e) Xu, Y.; Sun, Q.; Tan, T.-D.; Yang, M.-Y.; Yuan, P.; Wu, S.-Q.; Lu,
X.; Hong, X.; Ye, L.-W. Organocatalytic Enantioselective Conia-Ene-
Type Carbocyclization of Ynamide Cyclohexanones: Regiodivergent
Synthesis of Morphans and Normorphans. Angew. Chem., Int. Ed.
2019, 58, 16252−16259. (f) Zhou, B.; Zhang, Y.-Q.; Zhang, K.; Yang,
M.-Y.; Chen, Y.-B.; Li, Y.; Peng, Q.; Zhu, S.-F.; Zhou, Q.-L.; Ye, L.-W.
Stereoselective Synthesis of Medium Lactams Enabled by Metal-Free
Hydroalkoxylation/Stereospecific [1,3]-Rearrangement. Nat. Com-
mun. 2019, 10, 3234. (g) Li, L.; Zhu, X.-Q.; Zhang, Y.-Q.; Bu, H.-
Z.; Yuan, P.; Chen, J.; Su, J.; Deng, X.; Ye, L.-W. Metal-Free Alkene
Carbooxygenation Following Tandem Intramolecular Alkoxylation/
Claisen Rearrangement: Stereocontrolled Access to Bridged [4.2.1]
Lactones. Chem. Sci. 2019, 10, 3123−3129. (h) Zhou, B.; Li, L.; Zhu,
X.-Q.; Yan, J.-Z.; Guo, Y.-L.; Ye, L.-W. Yttrium-Catalyzed Intra-
molecular Hydroalkoxylation/Claisen Rearrangement Sequence:
Efficient Synthesis of Medium-Sized Lactams. Angew. Chem., Int. Ed.
2017, 56, 4015−4019. (i) Shen, W.-B.; Xiao, X.-Y.; Sun, Q.; Zhou, B.;
Zhu, X.-Q.; Yan, J.-Z.; Lu, X.; Ye, L.-W. Highly Site Selective Formal
[5 + 2] and [4 + 2] Annulations of Isoxazoles with Heterosubstituted
Alkynes by Platinum Catalysis: Rapid Access to Functionalized 1,3-
Oxazepines and 2,5-Dihydropyridines. Angew. Chem., Int. Ed. 2017,
56, 605−609. (j) Shen, W.-B.; Sun, Q.; Li, L.; Liu, X.; Zhou, B.; Yan,
J.-Z.; Lu, X.; Ye, L.-W. Divergent Synthesis of N-Heterocycles via
Controllable Cyclization of Azido-Diynes Catalyzed by Copper and
Gold. Nat. Commun. 2017, 8, 1748.
Carbometallation/Cyclization of Imine-ynamides with Arylboronic
Acids. Chem. Commun. 2020, 56, 4832−4835.
(11) For selected examples, see: (a) Trost, B. M.; Ryan, M. C. A
Ruthenium/Phosphoramidite-Catalyzed Asymmetric Interrupted
Metallo-ene Reaction. J. Am. Chem. Soc. 2016, 138, 2981−2984.
(b) Ye, L.; He, W.; Zhang, L. A Flexible and Stereoselective Synthesis
of Azetidin-3-ones through Gold-Catalyzed Intermolecular Oxidation
of Alkynes. Angew. Chem., Int. Ed. 2011, 50, 3236−3239. (c) Sun, P.;
Weinreb, S. M.; Shang, M. tert-Butylsulfonyl (Bus), a New Protecting
Group for Amines. J. Org. Chem. 1997, 62, 8604−8608.
(12) For details, please see the Supporting Information.
(13) CCDC 1813248, 1997538, 1997539, and 1812196 (2m, 4g,
4a′, and 6l, respectively) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre.
(14) For recent selected examples, see: (a) Lu, S.; Ong, J.-Y.; Poh, S.
B.; Tsang, T.; Zhao, Y. Transition-Metal-Free Decarboxylative
Propargylic Substitution/Cyclization with either Azolium Enolates
or Acyl Anions. Angew. Chem., Int. Ed. 2018, 57, 5714−5719.
(b) Jarrige, L.; Blanchard, F.; Masson, G. Enantioselective Organo-
catalytic Intramolecular Aza-Diels-Alder Reaction. Angew. Chem., Int.
Ed. 2017, 56, 10573−10576. (c) Li, M.-M.; Wei, Y.; Liu, J.; Chen, H.-
W.; Lu, L.-Q.; Xiao, W.-J. Sequential Visible-Light Photoactivation
and Palladium Catalysis Enabling Enantioselective [4 + 2] Cyclo-
additions. J. Am. Chem. Soc. 2017, 139, 14707−14713. (d) Lu, X.; Ge,
L.; Cheng, C.; Chen, J.; Cao, W.; Wu, X. Enantioselective Cascade
Reaction for Synthesis of Quinolinones through Synergistic Catalysis
Using Cu-Pybox and Chiral Benzotetramisole as Catalysts. Chem. −
Eur. J. 2017, 23, 7689−7693.
(15) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and
Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600−
3740. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. N-tert-
Butanesulfinyl Imines: Versatile Intermediates for the Asymmetric
Synthesis of Amines. Acc. Chem. Res. 2002, 35, 984−995.
(9) For selected examples, see: (a) Zhang, X.-Z.; Gan, K.-J.; Liu, X.-
X.; Deng, Y.-H.; Wang, F.-X.; Yu, K.-Y.; Zhang, J.; Fan, C.-A.
Enantioselective Synthesis of Functionalized 4-Aryl Hydrocoumarins
and 4-Aryl Hydroquinolin-2-ones via Intramolecular Vinylogous
Rauhut−Currier Reaction of para-Quinone Methides. Org. Lett.
2017, 19, 3207−3210. (b) Guan, M.; Pang, Y.; Zhang, J.; Zhao, Y. Pd-
Catalyzed Sequential β-C(sp3)-H Arylation and Intramolecular
Amination of δ-C(sp2)−H Bonds for Synthesis of Quinolinones via
an N, O-Bidentate Directing Group. Chem. Commun. 2016, 52,
7043−7046. (c) Ng, P. S.; Manjunatha, U. H.; Rao, S. P. S.; Camacho,
L. R.; Ma, N. L.; Herve, M.; Noble, C. G.; Goh, A.; Peukert, S.;
Diagana, T. T.; Smith, P. W.; Kondreddi, R. R. Structure Activity
Relationships of 4-Hydroxy-2-pyridones: A Novel Class of Anti-
tuberculosis Agents. Eur. J. Med. Chem. 2015, 106, 144−156.
(d) Mayr, F.; Wiegand, C.; Bach, T. Enantioselective, Intermolecular
[2 + 2] Photocycloaddition Reactions of 3-Acetoxyquinolone: Total
Synthesis of (−)-Pinolinone. Chem. Commun. 2014, 50, 3353−3355.
(e) Chen, Y. F.; Lin, Y. C.; Huang, P. K.; Chan, H. C.; Kuo, S. C.;
Lee, K. H.; Huang, L. J. Design and Synthesis of 6,7-Methylenedioxy-
4-substituted Phenylquinolin-2(1H)-one Derivatives as Novel Anti-
cancer Agents that Induce Apoptosis with Cell Cycle Arrest at G2/M
Phase. Bioorg. Med. Chem. 2013, 21, 5064−5075. (f) Mehta, M.;
Keisinger, J. W.; Zhang, X. P.; Lerner, M. L.; Brackett, D. J.;
Brueggemeier, R. W.; Li, P.-K.; Pento, J. T. Influence of novel KGFR
tyrosine kinase inhibitors on KGF-mediated proliferation of breast
cancer. Anticancer Res. 2010, 30, 4883. (g) Kobayashi, Y.; Harayama,
T. Triflic Anhydride-Mediated Tandem Formylation/Cyclization of
Cyanoacetanilides: A Concise Synthesis of Glycocitlone Alkaloids.
Tetrahedron Lett. 2009, 50, 6665−6667. (h) Williams, T. M.; Burgey,
C. S.; Tucker, T. J.; Stump, C. A.; Bell, I. M. PCT Int. Appl. WO
2,006,031,606A2, 2006. (i) Cheon, S. H.; Lee, J. Y.; Chung, B.-H.;
Choi, B.-G.; Cho, W.-J.; Kim, T. S. Studies on the Synthesis and in
Vitro Antitumor Activity of the Isoquinolone Derivatives. Arch.
Pharm. Res. 1999, 22, 179−183.
(16) For a Sc(OTf)3-catalyzed intermolecular hydrative aldol
reaction of ynamides with ketones, see: Liu, Y.-W.; Mao, Z.-Y.; Nie,
X.-D.; Si, C.-M.; Wei, B.-G.; Lin, G.-Q. Approach to Tertiary-Type β-
Hydroxyl Carboxamides through Sc(OTf)3-Catalyzed Addition of
Ynamides and Ketones. J. Org. Chem. 2019, 84, 16254−16261.
(17) For a ZnBr2-catalyzed synthesis of coumarins from ynamides
and salicylaldehydes, see: Yoo, H. J.; Youn, S. W. Zn(II)-Catalyzed
One-Pot Synthesis of Coumarins from Ynamides and Salicylalde-
hydes. Org. Lett. 2019, 21, 3422−3426.
(18) For recent selected examples, see: (a) Li, G.-T.; Li, Z.-K.; Gu,
Q.; You, S.-L. Asymmetric Synthesis of 4-Aryl-3,4-dihydrocoumarins
by N-Heterocyclic Carbene Catalyzed Annulation of Phenols with
Enals. Org. Lett. 2017, 19, 1318−1321. (b) Wu, Z.; Wang, X.; Li, F.;
Wu, J.; Wang, J. Chemoselective N-Heterocyclic Carbene-Catalyzed
Cascade of Enals with Nitroalkenes. Org. Lett. 2015, 17, 3588−3591.
(c) Niharika, P.; Ramulu, B. V.; Satyanarayana, G. Lewis Acid
Promoted Dual Bond Formation: Facile Synthesis of Dihydrocoumar-
ins and Spiro-tetracyclic Dihydrocoumarins. Org. Biomol. Chem. 2014,
12, 4347−4360. (d) Lee, J.-W.; List, B. Deracemization of α-Aryl
Hydrocoumarins via Catalytic Asymmetric Protonation of Ketene
Dithioacetals. J. Am. Chem. Soc. 2012, 134, 18245−18248.
(19) Mita, T.; Higuchi, Y.; Sato, Y. One-Step Synthesis of Racemic
α-Amino Acids from Aldehydes, Amine Components, and Gaseous
CO2 by the Aid of a Bismetal Reagent. Chem. - Eur J. 2013, 19, 1123−
1128.
(20) (a) Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O.
Efficient Entry into 2-Substituted Tetrahydroquinoline Systems
through Alkylative Ring Expansion: Stereoselective Formal Synthesis
of ( )-Martinellic Acid. J. Org. Chem. 2010, 75, 914−921. (b) Snider,
B. B.; Ahn, Y.; O’Hare, S. M. Total Synthesis of ( )-Martinellic Acid.
Org. Lett. 2001, 3, 4217−4220.
1
(21) H NMR monitoring of these hydrative cyclizations under the
standard conditions revealed that the formation of trans-2a, trans-6a,
and cis-4a was not observed as intermediates.
(10) Wang, H.-R.; Huang, E.-H.; Luo, C.; Luo, W.-F.; Xu, Y.; Qian,
P.-C.; Zhou, J.-M.; Ye, L.-W. Copper-catalyzed Tandem cis-
1713
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ACS Catal. 2021, 11, 1706−1713