General Synthesis of α-Alkyl Ynones from Morpholine Amides and 1-Copper(I) Alkynes Promoted by Triflic Anhydride

Article abstract of DOI:10.1021/acs.orglett.0c02944

The first general method for the synthesis of α-alkyl ynones was developed based on the strategy of electrophilic activation of amides. Its distinctive advantages are attributed to the use of air-stable "bare"1-copper(I) alkyne as a mild nucleophile witho

Full text of DOI:10.1021/acs.orglett.0c02944

pubs.acs.org/OrgLett
Letter
General Synthesis of α‑Alkyl Ynones from Morpholine Amides and
1‑Copper(I) Alkynes Promoted by Triflic Anhydride
Yunxiang Weng, Lin Min, Xiaobao Zeng, Lidong Shan, Xinyan Wang,* and Yuefei Hu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02944
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The first general method for the synthesis of α-alkyl
ynones was developed based on the strategy of electrophilic
activation of amides. Its distinctive advantages are attributed to the
use of air-stable “bare” 1-copper(I) alkyne as a mild nucleophile
without any exogeneous ligand.
Scheme 2. Pioneering Works and This Work
nones (1 and 1′) are compounds with conjugated alkynyl
Yand carbonyl groups. They are recognized as versatile
synthons in organic synthesis and are responsible for numerous
synthetic methods.1,2 In the literature, great efforts have been
made to develop methods for the synthesis of ynones (1 and
1′), and the major methods include2 (a) acylation of 1-metal
alkynes with carboxylic acid derivatives; (b) Sonogashira
coupling of terminal alkynes with acyl chlorides; (c) transition-
metal-catalyzed carbonylation; (d) direct or indirect oxidation
of alkynes; and (e) acyl radical addition of alkynyl iodides3
(Scheme 1).
Scheme 1. Major Methods for Synthesis of Ynones (1 or 1′)
Their successes owe to the generation of an intermediate with
a stable tetrahedral metallic chelate by which the formation of
overaddition products can be prevented. However, these
methods have two drawbacks caused by the use of highly
reactive 1-metal alkynes: they must be operated under
anhydrous conditions and are incompatible with most
functional groups. Therefore, the development of convenient
methods for efficient synthesis of functionalized α-alkyl ynones
(1) is still a compelling problem.
Herein, we report a novel method for the synthesis of α-alkyl
ynones (1) from morpholine amides (2) and 1-copper(I)
alkynes (3) promoted by triflic anhydride (Tf2O) (Scheme
2c). Since 1-copper(I) alkynes (3) are air-stable solids with
mild nucleophilicity, this method can be conveniently operated
to give functionalized α-alkyl ynones (1) without any
overaddition product.
Ynones usually are divided into α-alkyl (1) and α-aryl
ynones (1′) because their behaviors are influenced significantly
by the substituent connected to the carbonyl group. The
synthesis of α-aryl ynones (1′) can be achieved easily using all
of the methods listed in Scheme 1, while the synthesis of α-
alkyl ynones (1) is still a challenging task due to the many
problems caused by the active methylene in both the substrate
and product. For example, Sonogashira coupling4 is the most
practical method for the synthesis of α-aryl ynones (1′), but it
is not suitable for α-alkyl ynones (1) with an active methylene.
Cox’s work5 revealed that this problem is caused by the tertiary
amine, which is used as an essential base for Sonogashira
coupling but incompatible with the active methylenes in
substrates (α-alkyl acyl chlorides) and products [α-alkyl
ynones (1)]. In practice, α-alkyl ynones (1) are often
synthesized by acylation of 1-metal alkynes (M = Li or Mg)
with Weinreb amides6 or morpholine amides7 (Scheme 2a,b).
Received: September 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02944
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
In recent years, the electrophilic activation of amides has
been applied widely in organic synthesis.8 Tf2O has been
recognized as the most practical activating agent to convert
amides into highly reactive iminium or keteniminium salts.9
On the basis of this strategy, several novel methods have been
developed to synthesize ketones from amides.10 As shown in
Scheme 3a, an amide 4 initially is activated by Tf2O to give an
Scheme 4. Primary Results from Conditional Tests
Scheme 3. Synthesis of Ketones Based on Electrophilic
Activation of Amides
a
Table 1. Results from the Conditional Tests
b
2a:3a:Tf2O (by
2-Cl-Pyr
(1.5 equiv)
temp
(°C)
time
(h)
1aa
entry
mol)
(%)
1
2
3
4
5
6
7
8
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.3/1.0/1.3
1.4/1.0/1.4
1.5/1.0/1.5
1.4/1.0/1.4
1.4/1.0/1.4
with
with
with
with
without
without
without
without
without
without
50
80
5
5
5
5
5
5
5
5
46
56
68
68
69
76
82
81
82
78
iminium triflate 5. It is then attacked by an organometallic
reagent to form an iminium triflate 6. Finally, a normal ketone
7 is obtained by an acidic hydrolysis of 6. Surprisingly, none of
the ynones (both 1 and 1′) were synthesized by these
methods, even though the alkynyl-substituted intermediate 6′
had been already prepared and transferred smoothly to other
products.10b,c,11 As shown in Scheme 3b, an imine product 8
was obtained by a basic hydrolysis of 6′ in Charette’s work,10c
while a β-chloroenone 9 was isolated by an acidic hydrolysis of
6′ in Huang’s work.10b Huang further proved that12 the desired
ynone was indeed produced from the acidic hydrolysis of 6′.
However, it was in situ converted into β-chloroenone 9 by an
acid-catalyzed hydrochlorination.13 Clearly, this problem
results from the fact that large amounts (two or more
equivalents) of halide anions are introduced into the reactions
by using halogen-containing 1-metal alkynes.10,11 The ideal
solution is use of the 1-metal alkynes without halide anions.
We realized that the “bare” 1-copper(I) alkynes may meet
this purpose. It is well-known14 that most 1-copper(I) alkynes
have polymeric structures as (RCCCu)n in which each
alkyne and Cu(I) coordinate each other by three C−Cu bonds.
Since there are no exogeneous ligands, these “bare” 1-
copper(I) alkynes are represented by a simple formula RC
CCu. They can be prepared as air-stable microcrystallines
within 1 h15 and stored at room temperature for many years. In
the past decade, 1-copper(I) alkynes have been widely used in
organic synthesis15−17 including some works from our
group.14,15a,17 Thus, we were encouraged to test a group of
conditional reactions between amides (4a−4c and 2a) and
copper(I) phenylethyne (3a). As shown in Scheme 4a, no
reaction occurred when the aryl amides 4a−4c were treated by
Tf2O and the yellow solid 3a was recovered in almost
quantitative yield (before the hydrolysis). To our delight, the
desired 1,5-diphenylpent-1-yn-3-one (1aa) was obtained in
46% yield from the reaction of 4-(3-phenylpropanoyl)-
morpholine (2a) and 3a (Scheme 4b).
100
110
100
100
100
100
100
100
9
10
1.5
1.0
a
The mixture of 2a, 3a (0.5 mmol), Tf2O with or without 2-
chloropridine in DCE (2 mL) was heated under the given conditions.
Then, the mixture was quenched by H2O (1 mL) at 50 °C for 30 min.
b
Isolated yields.
markedly by the ratio of 2a to 3a (entries 5−8). The highest
yield was obtained when 1.4 equiv of 2a were used (entry 7).
Similar excellent results were obtained when the reaction time
was reduced to 1.5 h (entry 9).
As shown in Table 2, all of the tested chloroalkanes were
suitable solvents and CHCl3 gave similar excellent results to
DCE (entries 1−3). CH3CN proved to be an unsuitable
solvent even though it has good solubility for both 2a and 3a
(entry 5). The results in entries 6−8 indicated that the
a
Table 2. Results from the Conditional Tests
b
entry
solvent
CHCl3
CH2Cl2
ClCH2CHCl2
toluene
MeCN
DCE
hydrolysis (50 °C/30 min)
1aa (%)
1
2
3
4
5
6
7
8
H2O
H2O
H2O
H2O
H2O
H2O
1.0 M aq HCl
satd aq NaHCO3
82
71
66
62
29
82
81
75
The reaction conditions between 2a and 3a were then
further optimized. As shown in Table 1, the yield of 1aa
increased with an increase of the reaction temperature (entries
1−4). Although 2-chloropyridine was used as an essential weak
base to the known procedures,9,10 it proved to be unnecessary
in our experiment (entry 5). The yield of 1aa was influenced
DCE
DCE
a
The mixture of 2a (1.4 equiv), 3a (0.5 mmol), and Tf2O (1.4 equiv)
in DCE (2 mL) was heated at 100 °C for 1.5 h. Then the mixture was
hydrolyzed under the given conditions. The isolated yields.
b
B
https://dx.doi.org/10.1021/acs.orglett.0c02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
hydrolysis by H2O was the most convenient process (entry 6).
Thus, the result in entry 6 was assigned as standard condition
for further tests.
To generalize this method, the scopes of substrates and
products were tested under standard conditions. As shown in
Scheme 5, the desired products 1aa−1ar were synthesized
molecules contained versatile moieties of bromobenzene, nitro
benzene, and carboxylic esters. The desired bis-ynone 1aq was
obtained smoothly when bis(1-copper alkyne) 3q was used as
a substrate.
Next, the reaction of copper(I) phenylethyne (3a) with
different amides was tested (Figure 1). The synthesis of 1ba−
1da indicated that the length of the carbon chain has no
comparable effect on the reactions. By using the ester−amide
2e as a substrate, an ester group was easily introduced into the
product 1ea. However, two products 1fa and 10 were isolated
when cyclohexanecarboxamide 2f was used as a substrate.
Interestingly, the mixture of 1fa and 10 was produced again
when pure 10 was hydrolyzed under the similar conditions.
This result suggests that a hydrolysis equilibrium between 1fa
and 10 may exist and the enamine 10 is the precursor of 1fa.
The product 1ga bearing an iodobenzene may lead it to be a
suitable substrate for metal-catalyzed couplings. Under stand-
ard conditions, 1aa was prepared on a 3 g scale in 87% yield.
As shown in Figure 2, several structurally special substrates
could not be used in this method. No reaction occurred by
Scheme 5. Products Prepared by This Method
Figure 2. Unsuitable substrates for this method.
using pivalamide (2i) as a substrate, which suggests that at
least one α-hydrogen in amides is required. Complicated
mixtures were obtained when acrylamide (2j), (3-oxo-1-butyn-
1-yl)copper (3s), or (3-methoxy-3-oxo-1-propyn-1-yl)copper
(3t) was used as a substrate, which indicates that the
conjugated structures are unstable under standard conditions.
Although the amides 2k−2p have very similar structures to
2a, none of them can be used as an alternative to 2a to react
with 3a (Figure 3). The desired product 1aa was obtained in
smoothly by treatment of the amide 2a with the different 1-
copper(I) alkynes 3a−3r. No comparable electronic and steric
effects were observed from the products 1ad−1af bearing a
fluoro-substituted benzene ring. The products 1aj−1aq were
obtained in lower yields by using 1-copper(I) alkynes 3j−3q as
substrates. It is worth noting that the method includes the
synthesis of the products 1ah−1ai and 1an−1aq because their
Figure 3. Unsuitable substrates for this method.
Figure 1. Products prepared by this method.
C
https://dx.doi.org/10.1021/acs.orglett.0c02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
poor yields from 2m−2n because they are secondary amides.
Only complicated mixtures were obtained from 2o−2p
because 3a is not stable to the tertiary amine in 2o, while 2p
is not stable to Tf2O. Compared to 2k−2l, the best results
were obtained from 2a possibly because the morpholine in 2a
is miscible with water and its oxygen atom can form hydrogen
bond with water, by which morpholine served as an efficient
leaving group in the hydrolysis step.
In conclusion, a general synthesis of α-alkyl ynones was
developed by the reaction of 1-copper(I) alkynes and amides
promoted by Tf2O. In this method, the “bare” 1-copper(I)
alkynes were used as an ideal source of alkynyls to demonstrate
three distinctive advantages: (a) they are air-stable organo-
metallic reagents that enable the method proceeding under
extremely convenient conditions; (b) they are mild nucleo-
philes that enable forming functionalized products directly
without the formation of the overaddition products; and (c)
they are readily accessible reagents that enable this method to
possess a wide diversity of substrates and products. In fact, this
method offers the first example for the synthesis of α-alkyl
ynones based on the strategy of electrophilic activation of
amides.
To further understand the reaction mechanism, more
conditional tests were made. As shown in Scheme 6a, the
Scheme 6. Group of Further Conditional Tests
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02944.
1
Experiments, characterization, and H and 13C NMR
spectra for all products 1aa−1ar, 1ba−1ga, 1dj, 1bm,
1ho, 10, 12, and 1ca-d1 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
desired product 1aa was obtained in only 23% yield from the
reaction of 2a and phenylethyne (11) catalyzed by CuI (10
mol %). This result indicates that there is no efficient catalytic
cycle of Cu(I) species in this method. The α-amino alkyne 12
was obtained when the reaction of 2b and 3a was worked up
by a reduction with NaBH3CN instead of by a hydrolysis with
H2O (Scheme 6b), which confirms that there is a
corresponding imine intermediate in this method. When the
reaction of 2c and 3a was worked up with D2O, a mixture of
1ca and 1ca-d1 was obtained (Scheme 6c). This result suggests
that the α-hydrogen in 2c participates in this method.
Xinyan Wang − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing 100084,
P.R. China; orcid.org/0000-0002-7030-0418;
Email: wangxinyan@mail.tsinghua.edu.cn
Yuefei Hu − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing 100084,
P.R. China; orcid.org/0000-0002-0538-8492;
Email: yfh@mail.tsinghua.edu.cn
Thus, a possible pathway for our method is proposed
(Scheme 7). Initially, a morpholine amide 2 reacts with Tf2O
Authors
Yunxiang Weng − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, P.R. China
Scheme 7. Proposed Pathway for This Method
Lin Min − Key Laboratory of Bioorganic Phosphorus Chemistry
and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, P.R. China
Xiaobao Zeng − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, P.R. China
Lidong Shan − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, P.R. China
to form an iminium triflate 13. Then a highly reactive
keteniminium triflate 14 forms by the expulsion of TfOH from
13 promoted by traces of TfOH and heating.18 Next, the
central carbon of keteniminium 14 is attacked by 1-copper(I)
alkyne 3 to generate an amino-enyne 15. Finally, an acid-
catalyzed hydrolysis of 15 occurs to give the target product 1
via the intermediates 16 and 17. In this pathway, the formation
of a TfOH and TfOH-catalyzed equilibrium between 15 and
16 played important roles, by which all of the results in
Scheme 6 can be well explained.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02944
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by National Natural Science
Foundation of China (Nos. 21971138 and 21472107).
■
D
https://dx.doi.org/10.1021/acs.orglett.0c02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
4428. (d) Pace, V.; Holzer, W.; Olofsson, B. Increasing the Reactivity
of Amides towards Organometallic Reagents: An Overview. Adv.
Synth. Catal. 2014, 356, 3697−3736.
(9) Selected reviews: (a) Evano, G.; Lecomte, M.; Thilmany, P.;
Theunissen, C. Keteniminium Ions: Unique and Versatile Reactive
Intermediates for Chemical Synthesis. Synthesis 2017, 49, 3183−3214.
(b) Madelaine, C.; Valerio, V.; Maulide, N. Revisiting Keteniminium
Salts: More than the Nitrogen Analogs of Ketenes. Chem. - Asian J.
2011, 6, 2224−2239.
REFERENCES
■
́
(1) Selected reviews: (a) Fraile, A.; Parra, A.; Tortosa, M.; Aleman,
J. Organocatalytic Transformations of Alkynals, Alkynones, Proprio-
lates, and Related Electron-Deficient Alkynes. Tetrahedron 2014, 70,
9145−9173. (b) Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.
Sequential Addition and Cyclization Processes of α,β-Ynones and α,β-
Ynoates Containing Proximate Nucleophiles. Synthesis 2014, 46,
687−721. (c) Sengee, M.; Sydnes, L. K. Specific Conjugate Addition
to α,β-Acetylenic Ketones. Pure Appl. Chem. 2011, 83, 587−596.
(d) Arai, T.; Ikematsu, Y.; Suemitsu, Y. Nickel-Catalyzed Multi-
component Coupling Reaction using Ynones. Pure Appl. Chem. 2010,
82, 1485−1490.
(10) (a) Huang, P.-Q.; Wang, Y.; Xiao, K.-J.; Huang, Y.-H. A
General Method for the Direct Transformation of Common Tertiary
Amides into Ketones and Amines by Addition of Grignard Reagents.
Tetrahedron 2015, 71, 4248−4254. (b) Xiao, K.-J.; Wang, A.-E;
Huang, Y.-H.; Huang, P.-Q. Versatile and Direct Transformation of
Secondary Amides into Ketones by Deaminative Alkylation with
Organocerium Reagents. Asian J. Org. Chem. 2012, 1, 130−132.
(c) Bechara, W. S.; Pelletier, G.; Charette, A. B. Chemoselective
Synthesis of Ketones and Ketimines by Addition of Organometallic
Reagents to Secondary Amides. Nat. Chem. 2012, 4, 228−234.
(11) (a) Chen, H.; Huang, Y.-H.; Ye, J.-L.; Huang, P.-Q. Double
Addition of Alkynyllithium Reagents to Amides/Lactams: A Direct
and Flexible Synthesis of 3-Amino-1,4-diynes Bearing an Aza-
Quaternary Carbon Center. J. Org. Chem. 2019, 84, 9270−9281.
(b) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Direct,
One-pot Sequential Reductive Alkylation of Lactams/Amides with
Grignard and Organolithium Reagents through Lactam/Amide
Activation. Angew. Chem., Int. Ed. 2010, 49, 3037−3040. (c) Mo-
vassaghi, M.; Hill, M. D. Synthesis of Substituted Pyridine Derivatives
via the Ruthenium-Catalyzed Cycloisomerization of 3-Azadienynes. J.
Am. Chem. Soc. 2006, 128, 4592−4593.
́
(2) Selected reviews: (a) Najera, C.; Sydnes, L. K.; Yus, M.
Conjugated Ynones in Organic Synthesis. Chem. Rev. 2019, 119,
11110−11244. (b) Whittaker, R. E.; Dermenci, A.; Dong, G.
Synthesis of Ynones and Recent Application in Transition-Metal-
Catalyzed Reactions. Synthesis 2016, 48, 161−183.
(3) Methods a−d have been summarized in ref 2. Selected refs for
method e: (a) Zeng, X.; Liu, C.; Yang, W.; Wang, X.; Wang, X.; Hu,
Y. A General two-step one-pot Synthesis Process of Ynones from α-
Keto Acids and 1-Iodoalkynes. Chem. Commun. 2018, 54, 9517−
9520. (b) Mukherjee, S.; Garza-Sanchez, R. A.; Tlahuext-Aca, A.;
Glorius, F. Alkynylation of Csp2(O)−H Bonds Enabled by Photo-
redox-Mediated Hydrogen-Atom Transfer. Angew. Chem., Int. Ed.
2017, 56, 14723−14726. (c) Wang, P.-F.; Feng, Y.-S.; Cheng, Z.-F.;
Wu, Q.-M.; Wang, G.-Y.; Liu, L.-L.; Dai, J.-J.; Xu, J.; Xu, H.-J.
Transition-Metal-Free Synthesis of Ynones via Decarboxylative
Alkynylation of α-Keto Acids under Mild Conditions. J. Org. Chem.
2015, 80, 9314−9320. (d) Huang, H.; Zhang, G.; Chen, Y. Dual
Hypervalent Iodine(III) Reagents and Photoredox Catalysis Enable
Decarboxylative Ynonylation under Mild Conditions. Angew. Chem.,
Int. Ed. 2015, 54, 7872−7876. (e) Tan, H.; Li, H.; Ji, W.; Wang, L.
Sunlight-Driven Decarboxylative Alkynylation of α-Keto Acids with
Bromoacetylenes by Hypervalent Iodine Reagent Catalysis: A Facile
Approach to Ynones. Angew. Chem., Int. Ed. 2015, 54, 8374−8377.
(12) Xiao, K.; Huang, Y.; Huang, P. General Direct Transformation
of Secondary Amides to Ketones via Amide Activation. Huaxue
Xuebao 2012, 70, 1917−1922.
(13) Selected references: (a) Zeng, X.; Lu, Z.; Liu, S.; Hammond, G.
B.; Xu, B. Metal-free, Regio-, and Stereo-Controlled Hydrochlorina-
tion and Hydrobromination of Ynones and Ynamides. J. Org. Chem.
2017, 82, 13179−13187. (b) Semenova, I. S.; Yarovenko, V. N.;
Levchenko, K. S.; Krayushkin, M. M. Synthesis of 1,3-Thioxoketones
from Salicylaldehyde. Russ. Chem. Bull. 2013, 62, 1022−1025.
(c) Shchukin, A. O.; Vasilyev, A. V. Different Reactivities of Acetylene
Carbonyl Compounds under the Catalysis by Bronsted Superacids
and Lewis Acids. Appl. Catal., A 2008, 336, 140−147. (d) Kundu, N.
G.; Chaudhuri, L. N. Synthesis of Dimethoxypyrimidines and Uracils
with Novel C-5 Substituents. J. Chem. Soc., Perkin Trans. 1 1991,
1677−1682.
́
(4) Selected reviews: (a) Chinchilla, R.; Najera, C. Chemicals from
Alkynes with Palladium Catalysts. Chem. Rev. 2014, 114, 1783−1826.
(b) Chinchilla, R.; Najera, C. The Sonogashira Reaction: A Booming
́
Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, 107,
874−922. See also: (c) Tohda, Y.; Sonogashira, K.; Hagihara, N. A
Convenient Synthesis of 1-Alkynyl Ketones and 2-Alkynamides.
Synthesis 1977, 1977, 777−778.
(5) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.; Charmant, J. P.
H.; Kantacha, A. Room Temperature Palladium Catalysed Coupling
of Acyl Chlorides with Terminal Alkynes. Chem. Commun. 2005,
1037−1039.
(14) For a review, see: Wang, X.; Wang, X.; Wang, X.; Zhang, J.; Liu,
C.; Hu, Y. In-situ Generated and Premade 1-Copper(I) Alkynes in
Cycloadditions. Chem. Rec. 2017, 17, 1231−1248.
(6) Selected reviews: (a) Senatore, R.; Ielo, L.; Monticelli, S.;
Castoldi, L.; Pace, V. Weinreb Amides as Privileged Acylating Agents
for Accessing α-Substituted Ketones. Synthesis 2019, 51, 2792−2808.
(b) Balasubramaniam, S.; Aidhen, I. S. The Growing Synthetic Utility
of the Weinreb Amide. Synthesis 2008, 3707−3738. See also:
(c) Nahm, S.; Weinreb, S. M. N-Methoxy-N-Methylamides as
Effective Acylating Agents. Tetrahedron Lett. 1981, 22, 3815−3818.
(7) Selected references: (a) Shin, W. K.; Kim, Y. R.; Im, S. H.; Jaladi,
A. K.; Gundeti, S.; An, D. K. An Efficient Protocol for the Preparation
of Ynones from Esters and Acid Chlorides. Bull. Korean Chem. Soc.
2018, 39, 683−686. (b) Jackson, M. M.; Leverett, C.; Toczko, J. F.;
Roberts, J. C. An Unexpected Equilibrium Process Associated with a
Standard Approach to Ynone Synthesis. J. Org. Chem. 2002, 67,
5032−5035. (c) Martín, R.; Romea, P.; Tey, C.; Urpí, F.; Vilarrasa, J.
Simple and Efficient Preparation of Ketones from Morpholine
Amides. Synlett 1997, 12, 1414−1416.
(8) Selected reviews: (a) Kaiser, D.; Bauer, A.; Lemmerer, M.;
Maulide, N. Amide Activation: an Emerging Tool for Chemoselective
Synthesis. Chem. Soc. Rev. 2018, 47, 7899−7925. (b) Huang, P.-Q.
Direct Transformations of Amides: Tactics and Recent Progress.
Huaxue Xuebao 2018, 76, 357−365. (c) Kaiser, D.; Maulide, N.
Making the Least Reactive Electrophile the First in Class: Domino
Electrophilic Activation of Amides. J. Org. Chem. 2016, 81, 4421−
(15) (a) Chen, W.; Wang, B.; Liu, N.; Huang, D.; Wang, X.; Hu, Y.
Tandem Synthesis of 3-Halo-5-Substituted Isoxazoles from 1-
Copper(I) Alkynes and Dihaloformaldoximes. Org. Lett. 2014, 16,
6140−6143. (b) Jouvin, K.; Heimburger, J.; Evano, G. Click-
alkynylation of N- and P-nucleophiles by oxidative cross-coupling
with alkynylcopper reagents: a general synthesis of ynamides and
alkynylphosphonates. Chem. Sci. 2012, 3, 756−760. (c) Owsley, D.
C.; Castro, C. E. Substitution of Aryl Halides with Copper(I)
Acetylides: 2-Phenylfuro [3,2-b] Pyridine. Org. Synth. Coll. 1972, 6,
916−918.
(16) Selected references: (a) Sagadevan, A.; Charpe, V. P.;
Ragupathi, A.; Hwang, K. C. Visible Light Copper Photoredox-
Catalyzed Aerobic Oxidative Coupling of Phenols and Terminal
Alkynes: Regioselective Synthesis of Functionalized Ketones via C≡C
Triple Bond Cleavage. J. Am. Chem. Soc. 2017, 139, 2896−2899.
(b) Ghiazza, C.; Billard, T.; Tlili, A. Trifluoromethyl- and
Fluoroalkylselenolations of Alkynyl Copper(I) Compounds. Chem. -
Eur. J. 2017, 23, 10013−10016. (c) Jiao, J.; Wang, S.; Chen, C.; Liu,
Q.; Xi, C. Directly Oxidative Cross-Coupling between Alkenylzirco-
nocene and Alkynylcopper Reagents. Organometallics 2016, 35,
́
̌
́
1415−1419. (d) Blastik, Z. E.; Voltrova, S.; Matousek, V.; Jurasek,
E
https://dx.doi.org/10.1021/acs.orglett.0c02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
́
̌
́
B.; Manley, D. W.; Klepetarova, B.; Beier, P. Azidoperfluoroalkanes:
Synthesis and Application in Copper(I)-Catalyzed Azide−Alkyne
Cycloaddition. Angew. Chem., Int. Ed. 2017, 56, 346−349. (e) Han, F.;
Li, J.; Zhang, H.; Wang, T.; Lin, Z.; Xia, H. Reactions of
Osmabenzene with Silver/Copper Acetylides: From Metallabenzene
to Benzene. Chem. - Eur. J. 2015, 21, 565−567. (f) Sagadevan, A.;
Ragupathi, A.; Hwang, K. C. Photoinduced Copper-Catalyzed
Regioselective Synthesis of Indoles: Three-Component Coupling of
Arylamines, Terminal Alkynes, and Quinones. Angew. Chem., Int. Ed.
2015, 54, 13896−13901.
(17) (a) Wang, B.; Liu, N.; Chen, W.; Huang, D.; Wang, X.; Hu, Y.
Minutes Synthesis of 1,4,5-Trisubstituted 5-Dialkylamino-1,2,3-
triazoles by 1-Copper(I)-Alkyne Controlled Tandem Process. Adv.
Synth. Catal. 2015, 357, 401−407. (b) Chen, W.; Zhang, J.; Wang, B.;
Zhao, Z.; Wang, X.; Hu, Y. Tandem Synthesis of 3-Chloro-4-
iodoisoxazoles from 1-Copper(I) Alkynes, Dichloroformaldoxime,
and Molecular Iodine. J. Org. Chem. 2015, 80, 2413−2417. (c) Zhang,
J.; Chen, W.; Wang, B.; Zhao, Z.; Wang, X.; Hu, Y. One-pot Three-
Component Synthesis of 1,4,5-Trisubstituted 5-Iodo-1,2,3-Triazoles
from 1-Copper(I) Alkyne, Azide and Molecular Iodine. RSC Adv.
2015, 5, 14561−14566. (d) Wang, B.; Zhang, J.; Wang, X.; Liu, N.;
Chen, W.; Hu, Y. Tandem Reaction of 1-Copper(I) Alkynes for the
Synthesis of 1,4,5-Trisubstituted 5-Chloro-1,2,3-triazoles. J. Org.
Chem. 2013, 78, 10519−10523. (e) Wang, B.; Liu, N.; Shao, C.;
Zhang, Q.; Wang, X.; Hu, Y. Preparation of 1,4,5-Trisubstituted 5-
Acyl-1,2,3-triazoles by Selective Acylation between Copper(I)-
Carbon(sp) and Copper(I)-Carbon(sp2) Bonds with Acyl Chlorides.
Adv. Synth. Catal. 2013, 355, 2564−2568. (f) Wang, B.; Ahmed, M.
N.; Zhang, J.; Chen, W.; Wang, X.; Hu, Y. Easy Preparation of 1,4,5-
Trisubstituted 5-(2-Alkoxy-1,2-Dioxoethyl)-1,2,3-Triazoles by Che-
moselective Trapping of Copper(I)−Carbon Bond with Alkoxalyl
Chloride. Tetrahedron Lett. 2013, 54, 6097−6100.
(18) (a) Min, L.; Yang, W.; Weng, Y.; Zheng, W.; Wang, X.; Hu, Y.
A Method for Bischler−Napieralski-Type Synthesis of 3,4-Dihydroi-
soquinolines. Org. Lett. 2019, 21, 2574−2577. (b) Booth, B. L.;
Haszeldine, R. N.; Laali, K. Alkyltrifluoromethanesulphonates as
Alkylating Reagents for Aromatic Compounds. J. Chem. Soc., Perkin
Trans. 1 1980, 2887−2893.
F
https://dx.doi.org/10.1021/acs.orglett.0c02944
Org. Lett. XXXX, XXX, XXX−XXX