Access to Acyclic Z-Enediynes by Alkyne Trimerization: Cooperative Bimetallic Catalysis Using Air as the Oxidant

Article abstract of DOI:10.1002/anie.201608192

Presented herein is a mild, operationally simple, mix-and-go procedure for the synthesis of acyclic trisubstituted Z-enediynes, from readily available terminal alkynes, in good yields. This method stems from a serendipitous discovery, and makes use of cooperative palladium/copper bimetallic catalysis and air as an oxidant to effect an intriguing alkyne trimerization to yield the valuable Z-enediyne moiety.

Full text of DOI:10.1002/anie.201608192

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608192
German Edition: DOI: 10.1002/ange.201608192
Alkynes
Access to Acyclic Z-Enediynes by Alkyne Trimerization: Cooperative
Bimetallic Catalysis Using Air as the Oxidant
Jin Tu Danence Lee and Yu Zhao*
Abstract: Presented herein is a mild, operationally simple,
mix-and-go procedure for the synthesis of acyclic trisubstituted
Z-enediynes, from readily available terminal alkynes, in good
yields. This method stems from a serendipitous discovery, and
makes use of cooperative palladium/copper bimetallic catalysis
and air as an oxidant to effect an intriguing alkyne trimeriza-
tion to yield the valuable Z-enediyne moiety.
N
atural Z-enediynes are a class of compounds with excep-
tional anticancer properties.[1] The presence of cis-arranged
conjugated carbon–carbon bonds in these natural Z-ene-
diynes allows for Bergman cyclization,[2] thus generating
diradicals which may serve as potent warheads in cancer cell
destruction. The potency of these natural Z-enediynes in
fighting cancer cells have motivated numerous research
groups to synthesize small organic molecules bearing the Z-
enediyne framework, and to test these molecules for their
efficacy in cancer cell treatment. Several of these artificial Z-
enediynes, containing an acyclic Z-enediyne moiety, have
proven to be excellent warheads in cancer cell destruction.[3]
The development of practical methods for the synthesis of
acyclic Z-enediynes from commercially available starting
materials would thus be desirable in further advancing the
field of Z-enediyne anticancer research.
Various methods have been used in the synthesis of acyclic
Z-enediynes (Scheme 1).[4] Most of these methods, however,
require the use of precursors which are difficult to access or
pyrophoric in nature, and unavoidably generate waste in the
process. The use of a Sonogashira coupling, for instance,
requires the preparation and use of a geometrically pure (Z)-
1,2-dihaloethylene.[5] More recently, p-tolyl sulfoxide[6] and
phosphonium salts[7] have also been reported as precursors in
the synthesis of acyclic Z-enediynes. Besides requiring several
steps in the preparation of these precursors, the use of
pyrophoric organometallic reagents like butyl lithium and
lithium acetylides limits the application of these methods for
the synthesis of acyclic Z-enediynes for high-throughput drug
discovery. Herein, we reveal an operationally simple method
for the synthesis of acyclic Z-enediynes by trimerization of
commercially available terminal alkynes and it is effected by
Scheme 1. A comparison between known synthetic methods and this
work.
cooperative palladium/copper catalysis. This process utilizes
air as the oxidant and generates minimal waste along the way.
The concept of cooperative bimetallic catalysis[8] has been
successfully employed in classical reactions such as Sonoga-
shira coupling,[9] Wacker oxidation,[10] etc. In addition, great
advances, particularly in cooperative or synergistic palladium/
copper catalysis, have also been achieved in recent years.[11] In
our own studies, we attempted to perform a 1,4-addition of
phenylacetylene (1a) to cyclohexenone catalyzed by palla-
dium acetate and copper iodide in the presence of the 2,2’-
bipyridine ligand. Instead of obtaining the anticipated ynone
2, an unexpected product, (Z)-1,3,6-triphenylhexa-3-en-1,5-
diyne (3a), was isolated in 31% yield (Scheme 2). It is
noteworthy that the oxidative homodimerization of phenyl-
acetylene, catalyzed by copper and palladium, to yield the
Glaser–Hay-type diyne product 4 (for structure see Table 1) is
well-established in the literature.[12] In addition, palladium-
[*] J. T. D. Lee, Prof. Dr. Y. Zhao
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: zhaoyu@nus.edu.sg
Homepage: zhaoyu.science.nus.edu.sg
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608192.
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3a (entries 10–12). In fact, the use of these oxidants resulted
in an unwanted increase in the formation of the 1,4-
diphenylbutadiyne side product 4. Air thus remained the
best oxidant for this transformation. In addition, performing
the reaction under the strict exclusion of air led a dramatic
decrease in yield to less than 5% (entry 13), thus confirming
the need for air as an oxidant for this transformation.
Scheme 2. The discovery of the unexpected trimerization of phenyl-
Further to this, the catalytic loadings of Pd(OAc)2, CuI,
and 2,2’-bipyridine were optimized. During the optimization,
it was observed that both the increase in the loading of
Pd(OAc)2 (Table 1, entry 14), and the decrease in the loading
of CuI (entry 15), led to a slight decrease in yield. Through
decreasing the loading of Pd(OAc)2 to 5 mol% and increasing
the loading of CuI to 10 mol%, an improvement in yield of 3a
to 64% was obtained (entry 17). A loading of 10 mol% 2,2’-
bipyridine led to an optimized yield of 70% (entry 18). The
optimization process also revealed that the palladium/bipyr-
idine complex is likely an important catalytic species for this
transformation as attempts to coordinate 2,2’-bipyridine to
CuI prior to the addition of Pd(OAc)2 and phenylacetylene
substrate resulted in much lower yield (33%).
In an effort to further optimize the reaction, other
palladium salts and copper salts were screened. Pd(OAc)2
proved to be essential for this catalytic system to work
(Table 2, entries 1–5), while replacing CuI with other sub-
stitutes led to dismal results (entries 6 and 7). Similarly, the
use of other analogues of 2,2’-bipyridine (entries 8–10) and
other common bis(phosphine) ligands (entries 11–13) did not
acetylene.
catalyzed conversion of terminal alkynes into enynes is also
reported.[13] Furthermore, there have also been several
reports on transition-metal-catalyzed trimerization of alkynes
to form dienynes.[14] The formation of highly valuable
endiynes from trimerization of alkynes, however, is not
known, to the best of our knowledge. Recognizing the
immense potential of this method in providing a single-step
access to acyclic Z-enediynes by an operationally simple
“mix-and-go” procedure, systematic optimization was carried
out to improve the yield of 3a.
Notably, 3a cannot be formed when either Pd(OAc)2, CuI,
or 2,2’-bipyridine is absent (Table 1, entries 1–4), thus lending
weight to a bimetallic catalysis pathway for its formation.
Systematic screening of solvents revealed that a mixture of
acetonitrile/methanol (1:1) gave an improvement in the yield
to 45% (entries 5–9). With the best solvent system in hand,
different oxidants were screened. The use of oxygen, inor-
ganic oxidants like sodium nitrite, and organic oxidants like p-
benzoquinone all led to a significant reduction in the yield of
Table 1: Optimization of 3a formation by bimetallic catalysis.[a]
Table 2: Catalyst optimization for the formation of 3a by bimetallic
catalysis.[a]
Entry
x
y
z
Oxidant
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
7.5
0
7.5
7.5
0
9
9
9
0
9
9
9
9
9
9
9
9
9
9
9
5
5
air
air
air
air
air
air
air
air
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
THF
toluene
DMSO
31
<2
<2
<2
34
15
<5
13
45
39
21
<2
<5
42
42
45
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
10
7.5
5
5
5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
5
Entry
Pd salt
Cu salt
Ligand
Yield [%][b]
air
O2
NaNO2
CH3CN/MeOH[c]
CH3CN/MeOH[c]
CH3CN/MeOH[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2
PdCl2
CuI
CuI
CuI
CuI
CuI
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
A
A
A
A
A
A
A
B
C
D
E
70
<2
<2
<2
<5
38
<2
48
45
p-quinone CH3CN/MeOH[c]
PdCl2(CH3CN)2
[Pd2(dba)3]
[Pd(PPh3)4]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
air
air
air
air
CH3CN/MeOH[c]
CH3CN/MeOH[c]
CH3CN/MeOH[c]
CH3CN/MeOH[c]
CH3CN/MeOH[c]
CH3CN/MeOH[c]
5
10
10
64
70
10 air
42
[a] Unless otherwise stated, reaction was performed by stirring the
catalysts and ligand in the solvent in a capped vial for 30 min followed by
the addition of 1a (1 mmol). [b] Determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as internal standard. [c] Used in a 1:1
ratio. DMSO=dimethylsulfoxide, THF=tetrahydrofuran.
<2
<2
<2
F
G
[a,b] See Table 1. dba=dibenzylideneacetone.
2
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improve the yield of 3a either. The original set of reaction
tolerated. In particular, para-bromophenylacetylene and
conditions in entry 1 remained optimal.
para-chlorophenylacetylene substrates led to good yields of
3e (67%) and 3 f (70%), respectively. Strongly electron-
withdrawing groups like fluorine, however, resulted in lower
yield (42% for 3g), although the presence of an additional
electron-donating group at the meta-position increased the
yield to 67% (3h). A meta-substituted electron-withdrawing
group is similarly well tolerated (3k), and ortho-substituted
groups, however, only led to the Glaser–Hay-type side
product. Besides phenylacetylene derivatives, the transfor-
mation also worked well for heterocycles like 3-ethynyl-
thiophene to deliver 3l in reasonable yield. Gratifyingly,
enynes such as 1-ethynylcyclohexene could also undergo
similar reaction to yield the endiyne 3m. Attempts to expand
the scope of this transformation to aliphatic alkynes, however,
were unsuccessful. In these cases, again the homodimerization
of alkynes took place predominantly to deliver the diyne side
product.
With the optimized reaction conditions in hand, the scope
of the transformation was investigated. As shown in
Scheme 3, substrates containing electron-donating groups in
the para- and meta-positions on the aryl ring were well
tolerated, thus giving rise to reasonable yields of 52 to 58%
(3b–d, 3i,j). Electron-withdrawing groups were similarly well
The possibility of obtaining a cross-trimerization product
was also carefully investigated by varying the electronic and/
or steric properties of the substrates. Reaction of electron-
poor para-bromophenylacetylene with the electron-rich para-
methoxyphenylacetylene under standard reaction conditions
led to a complex mixture of products containing homodimers,
heterodimers, homotrimers, and heterotrimers. Likewise, we
were unable to isolate any crosstrimerization products when
phenylacetylene was reacted with internal alkynes or ali-
phatic alkynes. The identification of a suitable catalytic
system for such challenging transformations will be the
focus of our future studies.
The structure and geometry of the endiyne product 3d
was unambiguously assigned by single-crystal X-ray analy-
sis.[16] The structures of the other products were assigned by
analogy based on the similarity of the peak pattern in the
NMR spectra.
Based on important precedents from the group of Trost[15]
and our experimental evidence, we propose the catalytic cycle
in Scheme 4 as a working hypothesis. The optimization studies
indicated that the palladium/bipyridine complex is formed
and is responsible for the reactivity. The proposed catalytic
cycle therefore begins with the formation of the complex I.
Direct deprotonation of a coordinated terminal alkyne by
acetate forms the 16-electron complex II. The introduction of
another molecule of alkyne results in an 18-electron complex
III which undergoes a carbopalladation step, in which the
palladium was placed at the less substituted carbon atom to
regenerate the more stable 16-electron complex IV. This
carbopalladation step is also the stereodetermining step for
this transformation. Following this, transmetallation of IV
with copper(I) acetylide generated from CuI and the sub-
strate leads to the formation of the intermediate V. Reductive
elimination of V then generates the desired product 3 and
a palladium(0) species VI. In another cooperative catalytic
cycle, copper(I) gets oxidized by oxygen in air to generate
a copper(II) species which oxidizes the palladium(0) species
VI to regenerate I.
There are two complications in this proposed catalytic
cycle. Firstly, the complex III could undergo further depro-
tonation of the coordinated terminal alkyne to form the
Scheme 3. Scope with respect to the Z-endiynes from alkyne trimeriza-
tion.
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chromatography using hexanes and ethyl acetate to afford 3 in pure
form.
Acknowledgments
We are grateful for the generous financial support from
Singapore National Research Foundation (R-143-000-477-
281), the Ministry of Education of Singapore (R-143-000-613-
112), and National University of Singapore (R-143-000-605-
112).
Keywords: alkynes · cooperative effects · copper · palladium ·
trimerization
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4
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Received: August 22, 2016
Published online: && &&, &&&&
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Alkynes
J. T. D. Lee, Y. Zhao*
&&&& — &&&&
Access to Acyclic Z-Enediynes by Alkyne
Trimerization: Cooperative Bimetallic
Catalysis Using Air as the Oxidant
Mix and go: Presented herein is a mild,
operationally simple, mix-and-go proce-
dure for the synthesis of acyclic trisub-
stituted Z-enediynes from readily avail-
able terminal alkynes in good yields. This
method stems from a serendipitous dis-
covery, and makes use of cooperative
palladium/copper bimetallic catalysis
and air as an oxidant to effect an
intriguing alkyne trimerization to yield the
valuable Z-enediyne moiety.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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