Ligand-Controlled Diastereoselective Cobalt-Catalysed Hydroalkynylation of Terminal Alkynes to E- or Z-1,3-Enynes

Article abstract of DOI:10.1002/chem.202001697

A diastereoselective hydroalkynylation of terminal alkynes to form the head-to-head dimerization products by two different cobalt-phosphine catalyst system is reported. The use of the bidentate ligand dppp and additional triphenylphosphine led to the selective formation of the (E)-1,3-enynes (E:Z>99:1) in good to excellent yields, while the tridentate ligand TriPhos led to the corresponding (Z)-1,3-enynes in moderate to good yields with excellent stereoselectivities (up to E:Z=1:99). Both pre-catalysts are easy to handle, because of their stability under atmospheric conditions. The optimized reaction conditions were identified by the Design of Experiments (DoE) approach, which has not been used before in cobalt-catalysed reaction optimisation. DoE decreased the number of required reactions to a minimum.

Full text of DOI:10.1002/chem.202001697

Accepted Article
Accepted Article
Title: Ligand-Controlled Diastereoselective Cobalt-Catalysed
Hydroalkynylation of Terminal Alkynes to E- or Z-1,3-Enynes
Authors: Gerhard Hilt, Sebastian M. Weber, and Jona Queder
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To be cited as: Chem. Eur. J. 10.1002/chem.202001697
Link to VoR: https://doi.org/10.1002/chem.202001697
01/2020

10.1002/chem.202001697
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Ligand-Controlled Diastereoselective Cobalt-Catalysed
Hydroalkynylation of Terminal Alkynes to E- or Z-1,3-Enynes
Sebastian M. Weber,[a,b] Jona Queder,[b] and Gerhard Hilt*[b]
[a]
[b]
Institut für Chemie, Carl von Ossietzky Universität Oldenburg
Carl-von-Ossietzky Straße 9-11, 26129 Oldenburg, Germany
E-mail: Gerhard.Hilt@uni-oldenburg.de
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: A diastereoselective hydroalkynylation of terminal alkynes
to form the head-to-head dimerization products by two different
cobalt-phosphine catalyst system is reported. The use of the bidentate
ligand dppp and additional triphenylphosphine led to the selective
formation of the (E)-1,3-enynes (E:Z > 99:1) in good to excellent yields,
while the tridentate ligand TriPhos led to the corresponding (Z)-1,3-
enynes in moderate to good yields with excellent stereoselectivities
(up to E:Z = 1:99). Both pre-catalysts are easy to handle, because of
their stability under atmospheric conditions. The optimized reaction
conditions were identified by the Design of Experiments (DoE)
approach, which has not been used before in cobalt-catalysed
reaction optimisation. DoE decreased the number of required
reactions to a minimum.
to excellent yields.[5] Recently, an iron(II) catalysed approach
towards products of type 1 was investigated by Song.[6] Cobalt-
hydride[7] and cobalt-phosphine catalysts in combination with
visible light[8] were utilized to generate the products of type 2
whereas the formation of the Z-configured enynes of type 3 has
been reported for e.g. iron-[9] and lanthanide-based[10] catalyst
systems. An (E)-selective cross-hydroalkynylation was reported
very recently where a cobalt(0/+II) couple was proposed to be the
catalytic species in a cross-dimerization of a terminal alkyne with
a bulky group, such as Me3Si and another sterically less-hindered
terminal alkyne (Scheme 2).[11]
Alkynes are versatile building blocks to construct various types of
cyclic and acyclic molecules. The dimerization of alkynes can lead
in rare occasions to transition-metal stabilized anti-aromatic
cyclobutadiene complexes or to acyclic dimers.[1] The transition-
metal catalysed addition of an unsymmetrical alkyne to itself, the
so called hydroalkynylation (dimerization), can be realized to
generate three possible products (Scheme 1).
Scheme 1. Possible hydroalkynylation products of terminal alkynes.
The transition-metal catalysed Markovnikov-type addition (head-
to-tail) leads to the conjugated enyne 1 whereas the anti-
Markovnikov addition generates either the E- or the Z-configured
enynes 2 and 3 (head-to-head products). For the selective
formation of only one of these products the catalyst must control
the regio- and the stereochemistry of this transformation.[2] Also,
the catalyst must allow the coordination of two alkynes to the
transition metal but not the incorporation of a third alkyne which
would lead to the well-known cyclotrimerization[3,4] towards arenes
or an undesired polymerization towards polyacetylenes. In the
past, excellent results for the dimerization of terminal alkynes
were obtained when precious metal catalysts, e.g. Pd, were
applied to realize the hydroalkynylation products of type 1 in good
Scheme 2. Recent progress on transition metal catalysed (cross)-
hydroalkynylation of terminal alkynes.[7,9,11]
Considering our ongoing interest in cobalt-catalysed reactions,
we experienced in several investigations that the choice of the
ligand, and the resulting new coordination sphere, is very decisive
for the preference for a single reaction pathway. Rather small
1
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changes can have a profound impact on the chemo, regio, or
stereoselective outcome of cobalt-catalysed reactions.[12-14]
Accordingly, the herein presented investigation was initiated by
the observation of a dimerization product when an additional
ligand was added to a simple cobalt catalyst for the desired
cyclotrimerization reaction of a terminal alkyne utilizing dppp (1,3-
bis(diphenylphosphino)-propane as the bidentate ligand. At first,
triethylamine was used as an additive, which could also act as a
base for a possible deprotonation of the alkyne coordinated to the
cobalt centre. Thereafter, we tested a variety of other nitrogen and
phosphorous donor ligands as additives to alter the reaction
pathway from the original [2+2+2] cycloaddition reaction towards
a hydroalkynylation of alkynes. Besides triethylamine, other
simple amines resulted already in good results, but the addition of
triphenylphosphine as the co-ligand gave the best results,
concerning yield and selectivity towards the E-1,3-enyne 2. In the
past, we experienced that the use of pyridine-imine-type ligands
resulted in a highly selective cyclotrimerization of terminal and
internal alkynes.[15] However, the use of additional ligands in
cobalt-pyridine-imine-type or pyridine-diimine pincer-type catalyst
systems did not result in an altered reaction pathway towards the
desired dimerization (hydroalkynylation) of alkynes. After
identification of the best bidentate ligand (dppp) and additive
(PPh3) for the products of type 2 we optimized the reaction
conditions by the Design of Experiments (DoE) approach[15] using
4-fluoro-1-ethynylbenzene as test substrate, regarding the
following parameters: catalyst loading (2 – 10 mol%, continuous),
PPh3 equivalents (1.0 – 3.0 equiv. related to the catalyst loading,
continuous), temperature (0 °C – 55 °C, continuous), time (0.5 h
– 6 h, continuous), substrate concentration (0.2 M – 1.5 M,
continuous) and zinc iodide (yes, no, categorical) were optimized
in only 25 experiments. Also, quadratic terms and possible cross
interaction between the parameters were considered. All other
categorical parameters, such as the solvent (THF, MeCN, CH2Cl2,
DMF) or cobalt source (CoBr2, CoCl2, Co(BF4)2, Co(ClO4)2), were
tested before starting with this D-optimal design (for further
information, see Supporting information, SI Table S1-S4).
Figure 1. Reaction optimization for the E-selective hydroalkynylation of terminal
alkynes. The predicted yields are plotted against the measured yields. Total run
of experiments: 31; 25 for the model, three duplicates for the lack of fit, and
three additional reactions for the PPh3 equivalents. The predicted optimized
reaction conditions can be seen in the boxes below. The yields were determined
by GC/FID analysis and 19F NMR spectroscopy using mesitylene and
hexafluorobenzene as internal standard.
The predicted reaction conditions show some similarities to the
described reaction conditions by Petit et al., who used a
preformed hydrido-cobalt(I) complex as active species (compare
Scheme 2).[7] We therefore conclude that cobalt(I) is the active
species which is easily generated in situ by reduction of the air
stable cobalt(II) pre-catalyst.
With the optimized conditions in hand, a variety of terminal
alkynes were transformed to synthesize the desired products of
type 2. Most strikingly, all the products were obtained in
outstanding E-selectivity (Scheme 3) and the products of type 1
or 3 were not observed at all.
After running the experiments (for the detailed reaction conditions,
see SI Table S5) three experiments were duplicated for the
determination of the lack of fit of the model (Figure 1).
The cobalt catalyst system tolerates a broad range of functional
groups, e.g. aryl halides (2b-2d) in good to excellent yields and
excellent regioselectivities. Besides simple alkyl groups (2e)
methoxy (2f), unprotected benzylic alcohols (2j), aldehyde (2h),
and ester substituents (2i) are well tolerated. The alkynyl arenes
with substituents in meta-position gave yields around 48%.
Normally, ortho-substituted alkynyl arenes with donor-
substituents in ortho-position cause more problems, due to their
steric demand near to the catalyst.[4,17] Interestingly, the products
2n and 2o gave considerably better yields between 70-72%
compared to those with the same substituents in meta-position
(2l/2m). Also, pyridinyl substituted alkynes were tolerated and
gave the desired products 2p/q in good yields, as well as the
ethynyl thiophene derivative which gave the products 2r in a
moderate yield. In addition, the rather volatile trieneyne 2s could
be isolated in 29% yield from the conjugated enyne and might be
of interest for follow-up reactions. It should be mentioned that the
yield also depends on the solubility of the reaction product in
acetonitrile. The highest yields were obtained, where the product
precipitates out of the reaction mixture (e.g. 2c and 2d).
Unfortunately, alkyl-substituted alkynes, such as 1-octyne or
cyclohexylacetylene gave no desired product. In case of 1-octyne
The resulting model consisted of eight factors with a R² = 0.95.
The most important factors were the temperature, the use of zinc
iodide, the cross interaction temperature • substrate concentration
and the catalyst loading (p-values < 0.01). Besides, the quadratic
terms of the substrate concentration (p-value = 0.01) and the
triphenylphosphine equivalents (p-value = 0.02) had also an
impact to the design.
Interestingly, the model shows that a low catalyst loading
(2.0 mol%) is optimal for the reaction with 4.5 mol% of
triphenylphosphine added to the catalyst. In contrast to our
previous reported reactions, containing cobalt catalysts and
alkynes, the use of zinc iodide has a counterproductive influence
concerning the yield, possibly indicating that one bromine atom
could stay at the central atom.
2
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only small amounts of the alkyne reacted after a long time, leading
only to the cyclotrimerization product. The cyclohexyl moiety led
to the formation of oligomers which were not characterized. The
use of trimethylsilyl acetylene gave similar results and pure
samples of the desired product (2v) could not be obtained.
Figure 2. Reaction optimization for the Z-selective hydroalkynylation of terminal
alkynes. The predicted yields are plotted against the measured yields. Total run
of experiments: 39; 30 for the design, six replicates for the lack of fit, and three
additional reactions with the optimized reaction conditions with different length
in time. The predicted optimized reaction conditions can be seen in the boxes
below. The yields were determined by GC/FID and 19F NMR spectroscopy using
mesitylene and hexafluorobenzene as internal standard
The original design consisted of only 16 reactions, where the
equivalent of zinc iodide was set between 4 – 60 mol%. Because
of the high significance of the quadratic term of the zinc iodide
equivalents, the range was expanded to 100 mol% and the design
was extended to consider all quadratic terms of each parameter
and possible cross interactions between them. The design
consisted of six factors with a R2 = 0.90. All p-values of the six
factors were lower than <0.01, showing that each factor is
important. The most important factor was the quadratic term of
zinc iodide equivalent, followed by the substrate concentration
and catalyst loading. The quadratic term of the temperature
indicated a slightly elevated temperature of 37 °C.
Scheme 3. Substrate scope of E-selective Hydroalkynylation of terminal
alkynes. All reactions were conducted on a 1.00 mmol scale. Yields are given
as isolated yields after purification via column chromatography. The substrates
2a and 2c were also synthesized in a gram-scale. The yields of the gram-scale
synthesis are given in parenthesis. [a] Reaction time: 18h [b] Reaction time:
48 h. [c] The product was obtained as an inseparable mixture of isomers.
In the next step of the investigation, the bidentate phosphine
ligand was exchanged to the more rigid tridentate linear TriPhos
ligand (see Scheme 3) which led surprisingly to the selective
formation of the Z-configured head-to-head dimerization product
of type 3, which has not been described in the literature before
using cobalt(0) or cobalt(I) catalyst systems. All other tested bi- or
tridentate phosphine ligands with different bite angles neither
changed the selectivity towards the Z-configured product, nor to
the head-to-tail dimerization product of type 1.
Next, we optimized the reaction conditions for the Z-selective
dimerization using the Design of Experiments approach. Before
running a D-optimal design, acetonitrile as solvent and cobalt
dibromide as cobalt source were set as standard conditions.
Unfortunately, no amine- or phosphine additive as ligand had a
positive effect to the reaction (see SI, Table S6-S8). All additives
led to a lower E/Z selectivity, so that no additive was added to the
model. Accordingly, the model consisted of the following
continuous parameters: catalyst loading (2 – 10 mol%), zinc
iodide (4 – 100%), temperature (−10 °C – 60 °C), substrate
concentration (0.2 M – 1.5 M) and time (3 h – 24 h). The results of
the D-optimal design are illustrated in Figure 2.
Under those optimized reaction conditions, the screening
substrate (4-fluoro-1-ethynylbenzene) showed full conversion
after three hours reaction time and the product 3b was isolated in
65% yield (predicted yield 67%).
With the optimized reaction conditions in hand, we started our
investigation concerning the substrate scope. While products 3a
and 3b were isolated in good yields with high Z-selectivities (up to
95:5), the products 3c, 3d and 3f were formed in lower E/Z ratios
and lower yields at 37 °C. Because of this observation, the
temperature was decreased to room temperature, resulting in
excellent selectivities and slightly increased yields. Compared
with the E-selective hydroalkynylation, the substrates 3a-3f gave
good yields between 64-69% and high preference for the Z-
configured products. While the ester substituted substrate 3i gave
a good yield of 67%, aldehyde, and alcohol moieties were not
tolerated. This could be explained by the need of the Lewis acid
ZnI2, leading to a full conversion towards polymers of unknown
constitution. A decrease of the amount of zinc iodide to 10 mol%
and an increased temperature of 37 °C resulted in the formation
of 3h in 14% yield and polymers as side products. Similar
observations were made for products 3p and 3q. Only 3-
3
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ethinylpyridine gave a low isolated yield (18%) of 3p.The ortho-
substituted products 3n and 3o needed longer reaction times and
showed lower E/Z-selectivities, possibly based on steric
interactions between the ligand-sphere of the active species and
the substrates. The products 3t and 3v could not be observed,
while 3u could be isolated as an E/Z mixture, accompanied with
the cyclotrimerization product. The catalyst system seems to
tolerate alkyl moieties and the optimization towards one reaction
pathway is under current investigation in our laboratory.
Mechanistic insights to the Z-selective dimerization process are under
investigation in our laboratory, concerning oxidation state and
intermediates of the active species.
In conclusion, we realized a diastereoselective synthesis of E- and Z-
enynes. To reduce the number of experiments of the optimization, we
performed the reaction optimization with the Design of Experiments
approach and identified the crucial parameters for both reactions. We
were able to generate the active cobalt species in an easy manner
without crucial decrease of the yield. Next, we have developed a novel
synthesis for Z-enynes, which includes cobalt(I) as the active species
for the first time. Both catalyst systems are kept simple considering
the possibility to reproduce the reported methods without the need of
strictly air- and moisture free conditions.
Acknowledgements
We thank Laura Sinatra for her help in designing the toc-graphic.
Keywords: alkynes • cobalt • design of experiments • enynes •
hydroalkynylation • stereoselectivity
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Scheme 3. Substrate scope of Z-selective hydroalkynylation of terminal alkynes.
All reactions were conducted on a 1.00 mmol scale. Yields are given as isolated
yields after purification via column chromatography. E/Z ratios are given in
parenthesis. [a] Temperature: 37 °C, reaction time: 3 h. [b] Reaction time: 24 h.
[c] Reaction time: 18 h. [d] Reaction time: 28 h. [e] Zinc iodide (10 mol%) was
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The change of the selectivity and the mechanism is not easy
explained. At first, we believe that the active species in both reaction
pathways needs a reduction step from cobalt(II) to cobalt(I) by the
reducing agent zinc. Stronger reducing agents like magnesium failed
in the Z-selective hydroalkynylation, leading to no product formation,
while ethyl magnesium bromide (2.0 equiv. referred to the catalyst
loading) leads to a lower conversion and lower yield of 3 (see SI, Table
S9). However, the higher amount of zinc iodide cannot be easily
explained. While the E-selective catalyst system could react via a
hydrocobaltation pathway as described by Petit et al.,[6] it is likely that
tridentate ligands may enable the formation of a cobalt-vinylidene
species, which leads to the selective formation of the Z-configured
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4
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[15] G. Hilt, T. Vogler, W. Hess, F. Galbiati, Chem. Commun. 2005, 1474-
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5
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Entry for the Table of Contents
Cobalt catalysis at a crossroad: The choice of the ligands in a cobalt-catalyzed hydroalkynylation of terminal alkynes is decisive to
form the dimerization products in a diastereoselective fashion. The (E)-1,3-enynes are formed in good to excellent yields and
outstanding selectivities (E:Z > 99:1), while the corresponding (Z)-1,3-enynes were isolated in moderate to good yields with excellent
stereoselectivities (up to E:Z = 1:99).
6
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