Ni/Cu-Catalyzed Decarboxylative Addition of Alkynoic Acids to Terminal Alkynes for the Synthesis of gem-1,3-Enynes

Article abstract of DOI:10.1021/acs.orglett.9b01625

The synthesis of gem-1,3-enynes via Ni/Cu-catalyzed decarboxylative addition of alkynoic acids to terminal alkynes has been developed. It was found that the decarboxylation of an alkynoic acid led predominantly to gem-1,3-enynes instead of 1,3-diynes, whi

Full text of DOI:10.1021/acs.orglett.9b01625

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni/Cu-Catalyzed Decarboxylative Addition of Alkynoic Acids to
Terminal Alkynes for the Synthesis of gem-1,3-Enynes
Sehyeon Han,† Han-Sung Kim,† Maosheng Zhang,‡ Yuanzhi Xia,*,‡ and Sunwoo Lee*,†
†Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, P. R. China
S
* Supporting Information
ABSTRACT: The synthesis of gem-1,3-enynes via Ni/Cu-catalyzed
decarboxylative addition of alkynoic acids to terminal alkynes has
been developed. It was found that the decarboxylation of an
alkynoic acid led predominantly to gem-1,3-enynes instead of 1,3-
diynes, which have been known to be formed through the coupling
of terminal alkynes. A variety of gem-1,3-enynes were obtained in
good yields. This catalytic system exhibited excellent regioselectivity
and high functional group tolerance.
onjugated 1,3-enynes are important structural units in
synthetic chemistry, materials science, and bioactive
successfully only using Rh,13 Ti,14 and Pd15 catalysts.
Moreover, all of these methods have been limited to terminal
alkynes.
C
product synthesis.1 A number of synthetic methods for the
preparation of 1,3-enynes have been reported,2 including the
Wittig reaction with propargyl aldehydes3 and dehydration of
propargyl alcohols4 (Scheme 1a,b). In terms of atom economy
We have been developing a number of synthetic methods
that use alkynoic acids, including transition metal-catalyzed
decarboxylative coupling reactions.16 Since simple preparation
methods for aryl alkynoic acid derivatives were reported,
decarboxylative reactions involving them have received much
attention and have been widely applied in organic synthesis.17
There are very few examples of metal-catalyzed coupling
reactions between alkynoic acids and terminal alkynes in which
they show different reactivity. Recently, we reported metal-free
synthesis of propargyl amines and selective synthesis of (Z)-
allyl nitriles and showed that only alkynoic acid derivatives
afforded the desired products under our optimal conditions.18
These results and the advantages of aryl alkynoic acids
stimulated our interest in developing new synthetic methods
using these compounds.
Scheme 1. Synthesis of 1,3-Enynes
In the course of our studies of novel reactions using alkynoic
acid derivatives, we found that alkynoic acids provide gem-1,3-
enynes when they are allowed to react with terminal alkynes in
the presence of Ni/Cu dual catalysts. Decarboxylative addition
was preferred, and this preference is not in agreement with
findings from other groups. Lei demonstrated that two
different terminal alkynes afforded 1,3-diynes in the presence
of Ni and Cu catalysts. In 2016, Zhou, Yin, and co-workers
reported the selective heterocoupling of terminal alkynes in the
presence of a copper catalyst (Scheme 2a).19 However, 1,3-
enynes were not found in either report. Hence, our finding is
very interesting and represents the first synthesis of gem-1,3-
enynes through a decarboxylative coupling reaction and the
and availability of starting materials, direct catalytic coupling is
very attractive. In this context, transition metal-catalyzed
reactions of alkenes with terminal alkynes and hydroalkynation
of alkynes have been developed (Scheme 1c).5 The cross-
dimerization of two different terminal alkynes has been
challenging because a number of isomers can be formed and
because it is difficult to control (Scheme 1d). To achieve
different chemo-, regio-, and stereoselectivities, Ir,6 Rh,7 Ru,8
Co,9 Fe,10 Pd,11 and Ni12 catalysts have been used. However,
gem-selective cross-dimerization of alkynes, which occurs
through head-to-tail cross-coupling, has been performed
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was employed as the solvent, the reaction improved
dramatically to give 3a in 69% yield (entry 10). Keeping
TMEDA as the solvent, we tested other copper sources,
namely, CuBr and CuCl, and other nickel sources, namely,
NiF2, NiBr2, NiI2, Ni(acac)2, and Ni(OAc)2. However, each
reaction gave poorer results (entries 11−17, respectively).
Keeping NiCl2·6H2O and CuI as the catalysts, we tested
different reaction temperatures. No products were found when
the reaction was conducted at 25 °C (entry 18). When the
reaction temperature was increased to 80 °C, 3a was afforded
in 85% yield and with less 4a (entry 19). Increasing the
reaction temperature to 100 °C decreased the yield of 3a and
resulted in a significant amount of byproduct 4a; however,
other isomers were not found (entry 20). In the absence of
CuI, only 3a was produced; however, its yield was low (entry
21). The reaction without NiCl2·6H2O provided 3a in only 9%
yield (entry 22). When the amount of Ni/Cu was decreased to
5 mol %, the yield decreased to 59% (entry 23). Character-
ization of decarboxylative addition product 3a was accom-
plished using 1H−13C heteronuclear multiple-bond correlation
(HMBC) experimental data. In addition, isomer 3a′ was not
found in any case (Figure 1). Finally, the optimal conditions
are as follows: 1.0 equiv of alkynoic acid, 3.0 equiv of terminal
alkyne, 10 mol % NiCl2·6H2O, and 10 mol % CuI in TMEDA
at 80 °C for 3 h.
Scheme 2. Synthesis of 1,3-Diyne and gem-1,3-Enyne
first example of nickel/copper-catalyzed synthesis of gem-1,3-
enynes. We envisioned that these intricate transformations
could be controlled at certain stages by tuning the reaction
parameters to furnish the desired products. Herein, we report
the selective synthesis of gem-1,3-enynes from alkynoic acids
and terminal alkynes using a nickel/copper catalyst (Scheme
2b).
To find the optimal conditions for the formation of gem-1,3-
enynes, p-tolylpropiolic acid (1a) and 2-methylbut-3-yn-2-ol
(2a) were chosen as standard substrates and evaluated with
varied parameters. The results are summarized in Table 1.
When 10 mol % NiCl2·6H2O and CuI were used as catalysts
with 10 mol % tetramethylethylenediamine (TMEDA) in
tetrahydrofuran (THF) at 50 °C, enyne 3a was produced in
45% yield. However, hetero-cross-coupling product 4a was also
found in 15% yield (entry 1). All tested ligands and solvents
provided unsatisfactory results (entries 2−9). When TMEDA
a
Table 1. Optimal Conditions for the Synthesis of gem-1,3-Enyne
b
yield (%)
entry
Ni
Cu
ligand
additive
temp (°C)
3a
4a
1
2
3
4
5
6
7
8
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiF2
NiBr2
NiI2
Ni(acac)2
Ni(OAc)2
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
−
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
−
TMEDA
bipyridine
1,10-Phen
PPh3
Xantphos
TMEDA
TMEDA
TMEDA
THF
THF
THF
THF
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
25
80
100
80
80
80
45
4
3
6
2
10
5
1
15
2
−
2
−
8
2
9
7
4
7
6
10
4
3
3
−
−
2
10
−
21
4
THF
toluene
CH3CN
dioxane
DMSO
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
9
TMEDA
2
10
11
12
13
−
−
−
−
−
−
−
−
−
−
−
−
−
−
69
37
6
2
c
14
43
36
5
15
16
17
18
19
20
21
22
2
−
85
65
45
9
CuI
CuI
d
23
NiCl2·6H2O
59
a
Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), Ni (0.03 mmol), Cu (0.03 mmol), and ligand (0.06 mmol) in solvent (1.0 mL) for 3 h.
b
c
d
Determined through gas chromatography and 1H nuclear magnetic resonance spectroscopy. NiBr2·O(CH2CH2OCH3)2 was used. Using 0.015
mmol of Ni and Cu.
B
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Aryl propiolic acids with a methoxy group at the para or meta
position afforded gem-1,3-enynes 3f and 3g in 79% and 62%
yields, respectively. However, the o-methoxyphenyl and
benzo[d][1,3]dioxol-4-yl propiolic acids provided 3h and 3i,
respectively, in slightly lower yields. Biphenyl and naphthyl
propiolic acids provided corresponding gem-1,3-enynes 3j and
3k in 86% and 82% yields, respectively. 2-Thiophenyl propiolic
acid gave 3l in 65% yield. Aryl propiolic acids featuring halide
groups such as bromide, chloride, and fluoride led to the
formation of corresponding gem-1,3-enynes 3m−3p in good
yields. 4-Trifluoromethylphenyl propiolic acid provided 3q in
72% yield. Aryl propiolic acids bearing electron-withdrawing
groups such as a ketone, an aldehyde, an ester, and a nitrile
were converted to corresponding products 3r−3u in 76%,
74%, 68%, and 65% yields, respectively. It was found that all
aryl propiolic acids afforded corresponding gem-1,3-enynes 3 as
the major products, and trace amounts of the corresponding
1,3-diynes 4 were detected. Unfortunately, alkyl-substituted
alkynoic acid such as 2-octynoic acid did not give the desired
product.
Figure 1. Isomers 3a and 3a′.
Using the optimal conditions, a variety of aryl propiolic acids
were evaluated for the reaction with propargyl alcohol 2a for
the formation of gem-1,3-enynes as shown in Scheme 3.
As expected, aryl alkynoic acids featuring alkyl groups such
as methyl or tert-butyl groups on the aryl ring reacted smoothly
to generate the corresponding products, 3a−3e in good yields.
Scheme 3. Synthesis of gem-1,3-Enynes from Aryl Propiolic
a
Acids and 2a
In addition to 2a, other terminal alkynes, namely, pent-4-yn-
1-ol, 1-phenylprop-2-yn-1-ol, 1-ethynylcyclohexanol, and ethy-
nylcyclohexane, were allowed to react with arylpropiolic acids,
viz., p-tolylpropiolic acid and 4-bromophenylpropiolic acid.
Scheme 4 shows that all terminal alkynes provided the
a
Scheme 4. Reactions with Other Terminal Alkynes
a
Reaction conditions: 1a (2.0 mmol), terminal alkyne (6.0 mmol),
NiCl2·6H2O (0.2 mmol), and CuI (0.2 mmol) in TMEDA (5.0 mL)
at 80 °C for 3 h.
corresponding gem-1,3-enynes. It was noteworthy that the
heterocoupling product, the 1,3-diyne, was not found in any
case. It was found that only one regioisomer formed and each
1
product was characterized using H−13C HMBC analysis (see
the Supporting Information). When phenyl acetylene and
trimethylsilyl acetylene were employed as terminal alkynes, the
1
corresponding gem-1,3-enynes were not detected via H NMR
analysis.
To study the different reactivities between terminal alkynes
and alkynoic acids, control experiments were conducted
(Scheme 5). When p-tolylacetylene (1a′) was employed
instead of p-tolylpropiolic acid under the standard conditions,
3a was not found; however, cross-coupling product 4a was
afforded in 14% yield. When the previously reported
conditions, which provided the cross-coupling products in
the reactions with terminal alkynes, were used in reactions
a
Reaction conditions: 1 (2.0 mmol), 2a (6.0 mmol), NiCl2·6H2O
(0.2 mmol), and CuI (0.2 mmol) in TMEDA (5.0 mL) at 80 °C for 3
h. Numbers in parentheses are the ratios of 3 to 4.
C
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
association of the L·HI moiety with Cu(I), as a higher barrier
was predicted if L·HI was removed. The direct coupling of
IM3 with 2a was found to be difficult; however, the
incorporation of Ni(II) through transmetalation via TS2 is
quite facile and affords more stable Ni(II)-acetylide
intermediates IM4 and IM5. The complexation of IM5 with
2a produces IM6 endergonically, and migratory insertion in
the latter intermediate occurs via TS3. This step requires an
overall activation barrier of 23.9 kcal/mol and generates
alkenyl Ni(II) intermediate IM7 highly exergonically. In the
last step, the protodemetalation could occur smoothly via TS4
if HCl is involved as the proton source. The resulting π
complex, IM8, undergoes dissociation favorably, forming 3a
and regenerating LNiCl2 with an overall exergonicity of 58.8
kcal/mol. The potential energy surface in Figure 2 suggests
that the Cu(I)-catalyzed decarboxylation step is relatively easy
and generates the acetylide irreversibly, while the Ni(II)-
catalyzed migratory insertion is the rate-determining step of
the entire reaction. Other possible pathways and isomeric TSs
were thoroughly studied using DFT but were found to be
higher in energy (more details are provided in the Supporting
Information). All of the DFT results corroborate the beneficial
combination of Ni(II) and Cu(I) for the generation of enynes
3 from 1 and 2.
In summary, we have found that reactions between alkynoic
acids and terminal alkynes in the presence of NiCl2·6H2O and
CuI provide decarboxylative head-to-tail dimerized products,
gem-1,3-enynes, in good yields. The employment of first-row
transition metals like nickel and copper for catalysts has
advantages. They are not only inexpensive because of their
abundance but also stable toward catalyst poisoning as a result
of heteroatom coordination. The reaction system uses mild
conditions and shows good functional group tolerance. It was
found that the nickel catalyst suppressed alkyne coupling,
which was dominated by the copper catalyst. Our findings were
different from those of reports that stated that two different
terminal alkynes coupled to give 1,3-diynes in the presence of a
Ni/Cu or Cu catalyst system. This was the first example of a
decarboxylative addition to an alkyne to afford a gem-1,3-
enyne. On the basis of DFT calculations, we suggested that
alkynyl copper is formed through decarboxylation and this is
followed by transmetalation to provide an alkynyl nickel
complex; in addition, Ni(II)-catalyzed migratory insertion is
the rate-determining step of the entire reaction.
Scheme 5. Control Experiments
between p-tolylpropiolic acid and 2a, neither 3a nor 4a was
found at 25 °C. However, 3a and 4a were formed with 20%
and 9% yields, respectively, when the reaction temperature
increased to 80 °C. To study the roles of nickel and copper, 1a
was treated with nickel and/or copper in the absence of 2a. No
homocoupling products 5a formed when a nickel-only catalyst
system was used. The reaction with the copper catalyst
afforded 5a in 60% yield. However, its yield decreased when
the nickel and copper catalysts were combined.
To better understand the experimental results, density
functional theory (DFT) calculations were carried out to shed
light on the exact mechanism of the transformation (Figure
2).20
ASSOCIATED CONTENT
■
S
* Supporting Information
Figure 2. DFT-computed mechanism for the Ni/Cu-catalyzed enyne
synthesis (L = TMEDA).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01625.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
The reaction conditions suggest that stable chelation
complexes LCuI and LNiCl2 (L = TMEDA) should be formed
favorably from the corresponding metals and TMEDA.
Theoretical results indicated that Cu(I) is more effective in
the decarboxylation process while Ni(II) is essential for the
coupling process. To start the reaction, complex IM1 could be
formed through the deprotonation of 1a by the basic solvent
(L). This step is endergonic by 7.9 kcal/mol. Prior to the
decarboxylation, IM2 could be formed via an interaction
between HL+ and iodide. The decarboxylation occurs via TS1
with an activation barrier of 20.0 kcal/mol, generating Cu(I)-
acetylide IM3 exergonically. This step is facilitated by the
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: xyz@wzu.edu.cn.
*E-mail: sunwoo@chonnam.ac.kr.
ORCID
Yuanzhi Xia: 0000-0003-2459-3296
Sunwoo Lee: 0000-0001-5079-3860
D
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Ito, J.-i.; Kitase, M.; Nishiyama, H. Cross-Coupling of Alkynes
Catalyzed by Phebox-Rhodium Acetate Complexes. Organometallics
2007, 26, 6412−6417.
Notes
The authors declare no competing financial interest.
(8) (a) Jun, C.-H.; Lu, Z.; Crabtree, R. H. Catalytic Head-to-Head
Alkyne Dimerizitbn to give Z-Enynes. Tetrahedron Lett. 1992, 33,
7119−7120. (b) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa, F. (Z)-
Selective cross-dimerization of arylacetylenes with silylacetylenes
catalyzed by vinylideneruthenium complexes. Chem. Commun. 2005,
4336−4338.
(9) Hilt, G.; Hess, W.; Vogler, T.; Hengst, C. Ligand and solvent
effects on cobalt(I)-catalysed reactions: Alkyne dimerisation versus [2
+ 2+2]-cyclotrimerisation versus Diels−Alder reaction versus [4 +
2+2]-cycloaddition. J. Organomet. Chem. 2005, 690, 5170−5181.
(10) Midya, G. C.; Paladhi, S.; Dhara, K.; Dash, J. Iron catalyzed
highly regioselective dimerization of terminal aryl alkynes. Chem.
Commun. 2011, 47, 6698−6700.
(11) Trost, B. M.; Sorum, M. T.; Chan, C.; Ruhter, G. Palladium-
̈
Catalyzed Additions of Terminal Alkynes to Acceptor Alkynes. J. Am.
Chem. Soc. 1997, 119, 698−708.
(12) Matsuyama, N.; Tsurugi, H.; Satoh, T.; Miura, M. Ligand-
Controlled Cross-Dimerization and -Trimerization of Alkynes under
Nickel Catalysis. Adv. Synth. Catal. 2008, 350, 2274−2278.
(13) (a) Ohshita, J.; Furumori, K.; Matsuguchi, A.; Ishikawa, M.
Synthesis and Reactions of (E)-1,4-Bis(silyl)-SubstituteEd nynes. J.
Org. Chem. 1990, 55, 3277−3280. (b) Boese, W. T.; Goldman, A. S.
Insert ion of Acetylenes into Carbon-Hydrogen Bonds Catalyzed by
Rhodium-Trimethylphosphine Complexes. Organometallics 1991, 10,
782−786. (c) Xu, H.-D.; Zhang, R. W.; Li, X.; Huang, S.; Tang, W.;
Hu, W.-H. Rhodium-Catalyzed Chemo- and Regioselective Cross-
Dimerization of Two Terminal Alkynes. Org. Lett. 2013, 15, 840−843.
(d) Azpiroz, R.; Rubio-Perez, L.; Castarlenas, R.; Perez-Torrente, J. J.;
Oro, L. A. gem-Selective Cross-Dimerization and Cross-Trimerization
of Alkynes with Silylacetylenes Promoted by a Rhodium−Pyridine−
N-Heterocyclic Carbene Catalyst. ChemCatChem 2014, 6, 2587−
2592.
(14) (a) Akita, M.; Yasuda, H.; Nakamura, A. Regioselective Homo-
and Codimerization of 1-Alkynes Leading to 2,4-Disubstituted 1-
Buten-3-ynes by Catalysis of a (η5-C5Me5)2TiCl2/RMgX system. Bull.
Chem. Soc. Jpn. 1984, 57, 480−487. (b) Oshovsky, G. V.; Hessen, B.;
Reek, J. N. H. B.; Bruin, B. de. Electronic Selectivity Tuning in
Titanium(III)-Catalyzed Acetylene Cross-Dimerization Reactions.
Organometallics 2011, 30, 6067−6070.
(15) (a) Sabourin, E. T. The selective head-to-tail dimerization of α-
hydroxy terminal acetylenes. J. Mol. Catal. 1984, 26, 363−373.
(b) Trost, B. M.; Chan, C.; Ruhter, G. Metal-Mediated Approach to
̈
Enynes. J. Am. Chem. Soc. 1987, 109, 3486−3487. (c) Chen, T.; Guo,
C.; Goto, M.; Han, L.-B. A Brønsted acid-catalyzed generation of
palladiumcomplexes: efficient head-to-tail dimerization of alkynes.
Chem. Commun. 2013, 49, 7498−7500. (d) Tsukada, N.; Ninomiya,
S.; Aoyama, Y.; Inoue, Y. Palladium-Catalyzed Selective Cross-
Addition of Triisopropylsilylacetylene to Internal and Terminal
Unactivated Alkynes. Org. Lett. 2007, 9, 2919−2921. (e) Tsukada,
N.; Ninomiya, S.; Aoyama, Y.; Inoue, Y. Palladium-catalyzed cross-
addition of triisopropylsilylacetylene to unactivated alkynes. Pure
Appl. Chem. 2008, 80, 1161−1166.
(16) (a) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H.
M.; Lee, S. One-Pot Synthesis of Diarylalkynes Using Palladium-
Catalyzed Sonogashira Reaction and Decarboxylative Coupling of sp
Carbon and sp2 Carbon. Org. Lett. 2008, 10, 945−948. (b) Park, K.;
Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. Synthesis of
Symmetrical and Unsymmetrical Diarylalkynes from Propiolic Acid
Using Palladium-Catalyzed Decarboxylative Coupling. J. Org. Chem.
2010, 75, 6244−9251. (c) Park, K.; Lee, S. Transition metal-catalyzed
decarboxylative coupling reactions of alkynyl carboxylic acids. RSC
Adv. 2013, 3, 14165−14182.
ACKNOWLEDGMENTS
■
This research was supported by National Research Foundation
of Korea (NRF) grants funded by the Korean government
( M S I P ) ( N R F - 2 0 1 2 M 3 A 7 B 4 0 4 9 6 5 5 , N R F -
2015R1A4A1041036, and NRF-2017R1A2B2002929). Y.X.
acknowledges financial support from NSFC (21873074 and
21572163). The spectral and HRMS data were obtained from
the Korea Basic Science Institute, Gwangju center, and Daegu
center.
REFERENCES
■
(1) (a) Goldberg, I. H. Mechanism of Neocarzinostatin Action: Role
of DNA Microstructure in Determination of Chemistry of Bistranded
Oxidative Damage. Acc. Chem. Res. 1991, 24, 191−198. (b) Nicolaou,
K. C.; Dai, W.-M.; Tsay, S.-C.; Estevez, V. A.; Wrasidlo, W. Designed
Enediynes: A New Class of DNA-Cleaving Molecules with Potent and
Selective Anticancer Activity. Science 1992, 256, 1172−1178.
(c) Rudi, A.; Schleyer, M.; Kashman, Y. Clathculins A and B, Two
Novel Nitrogen-Containing Metabolites from theSponge Clathrina
aff. Reticulum. J. Nat. Prod. 2000, 63, 1434−1436. (d) Fontana, A.;
d’Ippolito, G.; D’Souza, L.; Mollo, E.; Parameswaram, P. S.; Cimino,
G. New Acetogenin Peroxides from the Indian Sponge Acarnus
bicladotylota. J. Nat. Prod. 2001, 64, 131−133. (e) Campbell, K.;
Kuehl, C. J.; Ferguson, M. J.; Stang, P. J.; Tykwinski, R. R.
Coordination-Driven Self-Assembly: Solids with Bidirectional Poros-
ity. J. Am. Chem. Soc. 2002, 124, 7266−7267. (f) Kim, H.; Lee, H.;
Lee, D.; Kim, S.; Kim, D. Asymmetric Total Syntheses of (+)-3-(Z)-
Laureatin and (+)-3-(Z)-Isolaureatin by “Lone Pair-Lone Pair
Interaction-Controlled” Isomerization. J. Am. Chem. Soc. 2007, 129,
2269−2274. (g) Trost, B. M.; Masters, J. T. Transition metal-
catalyzed couplings of alkynes to 1,3-enynes: modern methods and
synthetic applications. Chem. Soc. Rev. 2016, 45, 2212−2238.
(2) (a) Saito, S.; Yamamoto, Y. The Dehydro-Diels-Alder Reaction.
Chem. Rev. 2000, 100, 2901−2915. (b) Zhou, Y.; Zhang, Y.; Wang, J.
Recent advances in transition-metal-catalyzed synthesis of conjugated
enynes. Org. Biomol. Chem. 2016, 14, 6638−6650.
̈
(3) (a) Deussen, H.-J.; Jeppesen, L.; Scharer, N.; Junager, F.;
Bentzen, B.; Weber, B.; Weil, V.; Mozer, S. J.; Sauerberg, P. Process
Development and Scale-Up of the PPAR Agonist NNC 61−4655.
Org. Process Res. Dev. 2004, 8, 363−371. (b) Hata, T.; Iwata, S.; Seto,
S.; Urabe, H. Iron-Catalyzed Synthesis of Allenes from 2-Alken-4-
ynoates and Grignard Reagents. Adv. Synth. Catal. 2012, 354, 1885−
1889. (c) Myrtle, J. D.; Beekman, A. M.; Barrow, R. A. Ravynic acid,
an antibiotic polyeneyne tetramic acid from Penicillium sp. elucidated
through synthesis. Org. Biomol. Chem. 2016, 14, 8253−8260. (d) Gao,
Z.; Fletcher, S. P. Construction of β to carbonyl stereogenic centres
by asymmetric 1,4-addition of alkylzirconocenes to dienones and
ynenones. Chem. Commun. 2018, 54, 3601−3604.
(4) (a) Yan, W.; Ye, X.; Akhmedov, N. G.; Petersen, J. L.; Shi, X.
1,2,3-Triazole: Unique Ligand in Promoting Iron-Catalyzed Propargyl
Alcohol Dehydration. Org. Lett. 2012, 14, 2358−2361. (b) Ye, C.;
Qian, B.; Li, Y.; Su, M.; Li, D.; Bao, H. Iron-Catalyzed Dehydrative
Alkylation of Propargyl Alcohol with Alkyl Peroxides To Form
Substituted 1,3-Enynes. Org. Lett. 2018, 20, 3202−3205.
(5) (a) Sakurada, T.; Sugiyama, Y.-k.; Okamoto, S. Cobalt-Catalyzed
Cross Addition of Silylacetylenes to Internal Alkynes. J. Org. Chem.
2013, 78, 3583−3591. (b) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y.
Iridium Complex-Catalyzed Cross-Coupling Reaction of Terminal
Alkynes with Internal Alkynes via C-H Activation of Terminal
Alkynes. Adv. Synth. Catal. 2005, 347, 872−876.
(17) (a) Park, K.; Palani, T.; Pyo, A.; Lee, S. Synthesis of aryl alkynyl
carboxylic acids and aryl alkynes from propiolic acid and aryl halides
by site selective coupling and decarboxylation. Tetrahedron Lett. 2012,
53, 733−737. (b) Park, K.; You, J.-M.; Jeon, S.; Lee, S. Palladium-
(6) Ogata, K.; Oka, O.; Toyota, A.; Suzuki, N.; Fukuzawa, S.-i.
Phosphine-Dependent Selective Cross-Dimerization between Termi-
nal Alkylacetylene and Silylacetylene by Iridium(I) Guanidinate
Complex−Phosphine System. Synlett 2008, 2008, 2663−2666.
E
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Catalyzed Sonogashira Reaction for the Synthesis of Arylalkynecar-
boxylic Acids from Aryl Bromides at Low Temperature. Eur. J. Org.
Chem. 2013, 2013, 1973−1978.
(18) (a) Park, K.; Heo, Y.; Lee, S. Metal-Free Decarboxylative
Three-Component Coupling Reaction for the Synthesis of Propargyl-
amines. Org. Lett. 2013, 15, 3322−3325. (b) Irudayanathan, F. M.;
Lee, S. Selective Synthesis of (E)- and (Z)-Allyl Nitriles via
Decarboxylative Reactions of Alkynyl Carboxylic Acids with Azobis-
(alkylcarbonitriles). Org. Lett. 2017, 19, 2318−2321.
(19) (a) Yin, W.; He, C.; Chen, M.; Zhang, H.; Lei, A. Nickel-
Catalyzed Oxidative Coupling Reactions of Two Different Terminal
Alkynes Using O2 as the Oxidant at Room Temperature: Facile
Syntheses of Unsymmetric 1,3-Diynes. Org. Lett. 2009, 11, 709−712.
(b) Su, L.; Dong, J.; Liu, L.; Sun, M.; Qiu, R.; Zhou, Y.; Yin, S. − F.
Copper Catalysis for Selective Heterocoupling of Terminal Alkynes. J.
Am. Chem. Soc. 2016, 138, 12348−12351.
(20) All DFT studies were done by optimization and frequency
calculations in the gas phase at the B3LYP/6-31G(d)/LANL2DZ
level, and solvation effect evaluation was performed by single-point
calculations at the (SMD)M06/6-311+G(d, p)/SDD level. All
energies given are relative free energies corrected with solvation
effects. Full computational details and results are given in the
Supporting Information.
F
DOI: 10.1021/acs.orglett.9b01625
Org. Lett. XXXX, XXX, XXX−XXX