Selective Synthesis of Tetrasubstituted Olefins by Copper-Mediated Acetoxythiolation of Internal Alkynes: Scope and Mechanistic Studies

Article abstract of DOI:10.1002/chem.201802546

The Cu-mediated synthesis of tetrasubstituted olefins by the addition of an acetate group and a thiolate to an unactivated internal alkyne is described. The reaction is fully stereoselective, because only the E alkene is obtained. If the alkyne is asymmetric, the reaction also shows a very high degree of regioselectivity. The mechanism of the reaction is elucidated by DFT methods, which show that it takes place through Cu-stabilized radical species. Calculations highlight the crucial role of the dimeric copper(II) diacetate in the process, as it generates the active species in which the sulfur center has an incipient thiyl radical character and accepting, through a series of changes in the oxidation states of the two copper centers, the two electrons released in the addition of two nucleophiles to the alkyne.

Full text of DOI:10.1002/chem.201802546

A Journal of
Accepted Article
Title: Selective synthesis of tetrasubstituted olefins by Cu-mediated
acetoxythiolation of internal alkynes: scope and mechanistic
studies
Authors: Esteban Pablo Urriolabeitia, Pedro Villuendas, Sara Ruiz,
Pietro Vidossich, and Agustí Lledós
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To be cited as: Chem. Eur. J. 10.1002/chem.201802546
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Supported by

10.1002/chem.201802546
Chemistry - A European Journal
FULL PAPER
Selective synthesis of tetrasubstituted olefins by Cu-mediated
acetoxythiolation of internal alkynes: scope and mechanistic
studies
Pedro Villuendas,[a] Sara Ruiz,[a] Pietro Vidossich,[b],[c] Agustí Lledós,*[b] and Esteban P. Urriolabeitia*[a]
Dedication ((optional))
Abstract: The Cu-mediated synthesis of tetrasubstituted olefins by
addition of an acetate group and a thiolate to an unactivated internal
alkyne is described. The reaction is fully stereoselective, because only
the E-alkene is obtained. When the alkyne is asymmetric, the reaction
shows also a very high degree of regioselectivity. The mechanism of
the reaction was elucidated by DFT methods and shows that it takes
place through a mechanism involving Cu-stabilized radical species.
Calculations highlight the crucial role of the dimeric copper(II)
diacetate in the process, generating the active species in which the
sulfur center has an incipient thiyl radical character and accepting,
through a series of changes in the oxidation states of the two copper
centers, the two electrons released in the addition of two nucleophiles
to the alkyne.
prevention of colorectal adenoma,[23] while Nileprost was
considered as a promising antiulcer agent.[24]
O
O
O
MeO2S
Me2N
Vioxx
Tamoxifen
CN
OH
C4H9
H
H
HO2C
Introduction
OH
Nileprost
H
The synthesis of tetrasubstituted olefins with complete control of
the regio- and stereoselectivities is still a challenge for synthetic
chemists, as it has been highlighted in recent revisions.[1-7] New
synthetic methods are continuously screened and an intensive
research, devoted to achieve more performant pathways while
keeping simple methodologies, is being developed.[8-18] The
interest in these particular substrates resides on their versatility
as starting materials, as well as in their pharmacological,
photochemical and electrochemical properties.[19-24] Just to
mention some well-known examples, (Z)-Tamoxifen (Figure 1) is
used in the treatment and prevention of breast cancer,[21] iso-
Combretastatine A-4 shows antitubulin activity,[22] Rofecoxib (a
selective inhibitor of cyclooxygenase-2) displays activity in the
Figure 1. Some examples of tetrasubstituted olefins with recognized
pharmacological activity
Some of the most general methods for the synthesis of
tetrasubstituted olefins involve addition reactions to internal
alkynes, usually carbometallations, which are followed by
oxidative couplings, cross couplings or addition of electrophiles.[8-
14]
Very recently, photoredox-based methods have also been
described.[17,18] These methods, however, suffer from some
disadvantages: (i) the main one is the highly reactive nature of the
organometallic reagents, difficult to handle and unable to be
transferred to an industrial scale due to the high costs; (ii) the poor
tolerance to the presence of reactive functional groups, due to
their nucleophilic character; (iii) the fact that olefins are usually
obtained as mixtures of Z/E-isomers, a problem which increases
as the number of different substituents increases. Therefore, as
stated above, the availability of tetrasubstituted alkenes with well-
defined geometry and good leaving groups, in order to be used
as building blocks, is still very limited.
[a]
[b]
[c]
Dr. P. Villuendas, Dr. S. Ruiz, Dr. E. P. Urriolabeitia
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)
CSIC-Universidad de Zaragoza, Facultad de Ciencias, Edificio D
Pedro Cerbuna 12, 50009 Zaragoza (Spain)
E-mail: esteban@unizar.es
Dr. Pietro Vidossich, Prof. Dr. A. Lledós
Departament de Química
Edifici Cn, Universitat Autònoma de Barcelona
08193 Cerdanyola del Vallés, Barcelona (Spain)
E-mail: agusti@klingon.uab.es
In this contribution, we present a simple method for the fully
stereo- and regioselective synthesis of tetrasubstituted E-olefins
containing two good leaving groups, a thiolate[25,26] and an
acetate.[27] The importance and the strategic interest of the thus
resulting vinyl sulfides[28] and vinyl acetates[29] as building blocks
in organic synthesis is considerable. The process is based on the
consecutive addition of two anionic functional groups, one sulfide
and one acetate, to an inactivated internal alkyne, promoted by a
commercially available salt of Cu(II), as is [Cu(OAc)2]2* (OAc =
Dr. Pietro Vidossich
COBO, Computational Bio-organic Chemistry Bogotá
Department of Chemistry
Universidad de los Andes
Carrera 1 No. 18A 10, 10 111711 Bogotá (Colombia)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201802546
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acetate, see Note at the end of the manuscript), under microwave
irradiation in short reaction times (Figure 2c). The detailed
mechanism of the reaction has been fully determined using DFT
methods and shows that the introduction of the sulfide is made, in
fact, in the form of a metal-stabilized radical and that the dimeric
nature of the copper reagent has a critical role in the promotion of
the reaction.
Previous work dealing with the simultaneous introduction of a
sulfide and another heteroatom-based functional group have
been reported to occur through one of the following two reactions.
The first method (a in Figure 2) is the metal-mediated addition of
a preformed S-X bond (X = heteroatom) to an internal alkyne,[4,30-
42] through either a mechanism involving radical species[34,37] or a
concerted molecular pathway.[35,36,38] That is, the reaction only
uses two components, the S-X source and the alkyne. For
instance, chlorothiolation or thioallylation processes have been
recently described.[4] The strong disadvantage of the method
resides in the fact that the S-X bond needs to be pre-formed and
usually it is rather unstable, as in the case of sulfenyl chlorides. In
this respect, there are no previous reports in the literature for the
addition of a S-O bond to an internal alkyne, probably due to the
intrinsic unstability of the starting material.
Due to this lack of efficient methods, we provide in this
contribution
a methodologically simple procedure for the
synthesis of tetrasubstituted olefins containing sulfides and
acetates as functional groups, avoiding prefunctionalization steps,
saving reaction time and chemicals, and minimizing waste, while
keeping the maximal selectivity (regio- and stereo), the widest
versatility and reaction scope, a process which takes place
through a different and novel radical-based mechanism.
Results and Discussion
1.- Synthesis and Characterization of Tetradentate
Olefins. We have first optimized the reaction conditions as
shown in Equation 1 and Table 1. Benzylmercaptan 1a was
reacted with 3-hexyne 2a (1:2 molar ratio), and with [Cu(OAc)2]2
(1 equiv.), using a microwave reactor, to yield selectively the (E)-
benzylthiohexenylacetate 3aa. Using hexafluoroisopropanol
(HFIP) as solvent we obtained a promising 38% yield of 3aa (entry
1) after chromatographic purification. In the spectroscopic
analysis of the crude only unreacted 1a was characterized
together with 3aa, and no traces of other isomers (cis-, gem-),
neither hydroarylation or bis-thiolation products, were observed.
Previous work
Et
[Cu(OAc)2]2
S
Et
SH
(1)
+
a) addition of preformed S-X bond to the internal alkyne: two components
solvent, µW (T ºC)
Et
30 min
R
R
R'S
R'S
X
Et
OAc
R'S-X
or
1a
2a
3aa
radical or
concerted
X
R
R
R
R
Table 1. Optimization for the synthesis of 3aa[a]
X = Cl, C, B, P, S
b) addition of thiirenium salts (electrophilic S+) to the alkyne: three components
Entry
Reagent
Solvent
HFIP
T (ºC)
100
100
100
100
120
140
Yield (%)
R'
S
R
R
R'S
1
2
3
4
5
6
[Cu(OAc)2]2
[Cu(OAc)2]2
[Cu(OAc)2]2
-
38
0
electrophilic S+
Nu-
R
toluene
MeOH
HFIP
Nu
R
R
R
0
This work
0
c) addition of one S-radical and one nucleophile to the alkyne: three components
CuI
R
R
R'S
CuII(OAc)
[Cu(OAc)2]2
[Cu(OAc)2]2
HFIP
66
34
R'SH
R
R'S
CuII(OAc)
- HOAc
-2 CuI
OAc
R
R
HFIP
R
7[b]
[Cu(OAc)2]2
+ NaOAc +
oxone
HFIP
120
0
Figure 2. Previous work and relationship with this one
8[b]
[Cu(OAc)2]2
+ PhI(OAc)2
HFIP
120
47
The second method (b in Figure 2) is by far the most developed
and starts with the generation of a highly electrophilic sulfur-
containing species, which further reacts with the alkyne to give a
thiirenium intermediate.[43-51] The olefin is eventually formed by
[a] 1 mmol of 1a, 2 mmol of 2a, 1 mmol of [Cu(OAc)2]2. [b] 5 mol% of
[Cu(OAc)2]2 and 1 equiv of oxidant and acetate source were used.
inter- or intramolecular reaction of the thiirenium with
a
nucleophile. In this case two different species provide one
fragment each, this fact resulting in a more versatile method.
However, the prefunctionalization of the sulfur reagent, aiming to
achieve a highly electrophilic species, is still mandatory. This
means additional reaction steps, expensive reagents and more
chemical waste. In addition, the formation of S- and O-substituted
alkenes using this method is scarcely represented.[44,48,49,51]
No conversion was observed when toluene or methanol were
used as solvents (entries 2, 3), as well as in other solvents
(regardless their protic/aprotic character and their polarity) such
as CH2Cl2 or THF. In the same way, the reaction does not
progress in the absence of the copper salt (entry 4). The
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10.1002/chem.201802546
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temperature and time were also tested and the optimized results
were 30 min at 120 °C (entries 5, 6). Longer reaction times or
higher temperatures are detrimental. Next, we examined the
influence of the acetate source and the possibility to perform the
reaction catalytically. The reaction was attempted using 5 mol%
[Cu(OAc)2]2 as catalyst and either oxone/NaOAc or PhI(OAc)2 as
oxidants/source of acetates in stoichiometric amounts (entries 7,
8). In the first case the result was negative, and 3aa was not
formed (entry 7). However, [Cu(OAc)2]2/PhI(OAc)2 was found as
a suitable catalytic system for this reaction (entry 8), showing the
same selectivity than pure [Cu(OAc)2]2, although affords 3aa with
structure of a quartet, due to the mutual coupling, being the
coupling constant 5JHH of 1.6 Hz. The high value measured for this
coupling constant is really diagnostic because, as it is reported in
the literature for (Z)- and (E)-isomers of 2-butene and also for
isomeric tiglic and angelic acids, the cis-arrangement (Z-olefin)
5
gives consistently values of the JHH constant around 1.2 Hz (or
even lower), while the trans (E)-isomers show values identical to
those here observed (1.6 Hz).[52-57] In addition, the regiochemistry
for 3ab and 3ae has been determined on the basis of the
correlations observed in the 1H-13C HMBC spectra. In the case of
3ab, the vinylic methyl (2.22 ppm) correlates with both olefinic
carbons (151.4 ppm, assigned to the C supporting the OAc group;
a
lower yield (47%). This lower yield, together with the
substantially higher price of PhI(OAc)2 compared with [Cu(OAc)2]2, and 130.7 ppm, assigned to the C bonded to the S-moiety), while
suggest that the best compromise is the use of 1 equivalent of the
copper salt. Once the optimized reaction conditions have been
determined, a series of internal alkynes 2a-2e were tested using
the optimized conditions (see Chart 1), and moderate to good
yields of the (E)-acetoxythiolated derivatives 3aa-3ae were
obtained.
the protons of the tBu group (1.22 ppm) only correlate with the C
at 130.7 ppm, showing that the BnS and tBu groups are on the
same olefinic carbon. In the case of 3ae a similar analysis has
been carried out using the =CMe and the ortho protons of the Bn
group (see SI). The reaction also tolerates the presence of
substituents in the phenyl ring (1a-1e), and good yields of 3ba-
t
3ea were obtained when alkyl groups (Me 1b, 1c; Bu 1d) or
strong electronwithdrawing groups (-CF3, 1e) were tested.
However, the use of strong electrondonating groups, such as
OMe, gave only small conversions (<5%) due to extensive
decomposition.
Thiophenols with different substituents 4a, 4d, 4f, 4g were also
reacted with alkynes 2a-2e, under the same reaction conditions,
to give the corresponding (E)-phenylthiohexenylacetates 5aa-5ae
and 5da-5ga in good to excellent yields (Chart 2).
R2
R1
R2
R1
SH
[Cu(OAc)2]2
OAc
+
S
HFIP µW 30 min
R3
R3
3aa-3ae; 3aa-3ea (9 examples)
(E)-stereoselective
1a-1e
2a-2e
OAc
OAc
OAc
OAc
S
S
S
3ab, 71%
regioselective
3aa, 66%
3ac, 75%
R1
R1
R2
SH
R2
[Cu(OAc)2]2
OAc
OAc
+
S
OAc
S
+
HFIP µW 30 min
S
S
R3
2a-2e
R3
5aa-5ae; 5da, 5fa, 5ga (8 examples)
(E)-stereoselective
3ae, 53%
regioselective
4a, 4d, 4f, 4g
3ad, 81% (both isomers)
OAc
S
OAc
OAc
OAc
S
S
OAc
OAc
S
S
S
5ab, 74%
5ac, 89%
3ca, 66%
3da, 61%
3ba, 76%
5aa, 87%
regioselective
OAc
S
OAc
OAc
+
OAc
F3C
S
S
S
3ea, 58%
5ae, 23% (30 min)
regioselective
5ad, 85% (both isomers)
Chart 1. Scope of the reaction of benzylmercaptanes 1 with internal alkynes 2.
Cl
MeO
OAc
OAc
OAc
S
S
S
When asymmetrical alkynes are used the reaction takes place
with full regioselectivity in the cases of 4,4-dimethyl-2-pentyne
(2b) or prop-1-ynyl-1-benzene (2e), affording the corresponding
E-alkenes 3ab and 3ae as single regioisomers. Instead, a mixture
of isomers was obtained with 2-hexyne (2d). The characterization
of the obtained olefins as (E)-isomers is based on the multiplicity
of the signals of the functional groups (methyl, ethyl) at the vinylic
carbons, and on the values of the homoallylic couplings JHH
determined for these signals. This is clearly seen in the case of
alkene 3ac, for which both methyl groups show a hyperfine
5ga, 41%
5da, 90%
5fa, 91%
Chart 2. Scope of the reaction of thiophenols 4 with internal alkynes 2.
As expected, the reaction of 4,4’-dimethyl-2-pentyne (5ab) and 1-
phenyl-1-propyne (5ae) were fully regioselective, although in the
latter the yield decreased notably. On the other hand, some
substituted thiophenols (4d, 4f, 4g) were tested in this reaction.
5
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Unlike mercaptans, thiophenols with electrondonating groups
such as p-OMe (4f) reacted efficiently and excellent yields were
observed. The yields dropped when o-Cl substituent was used
(4g), and no reaction was observed when other electron-poor
thiophenols as p-CF3C6H4SH (4e) or F5C6SH were used.
Therefore, the substituents in the aryl ring tune the reactivity of
the reaction, and this effect is more pronounced for thiophenols 4
than for benzylmercaptanes 1.
2.- Mechanistic Considerations. Aiming to get more insight in
the reaction and to explain the observed selectivities, we
undertook the study of its mechanism. When the reaction of
thiophenol 4a with alkyne 2a is carried out in presence of
stoichiometric amounts of a radical scavenger (TEMPO) the
reaction is completely quenched, and no conversion at all was
detected. Therefore, the reaction seems to take place through a
mechanism involving radicals in the case of thiophenol. When
benzylmercaptane 1a was reacted with alkyne 2a in the presence
of TEMPO a partial quench of the reaction was observed,
because a 34% yield of 3aa was obtained instead of the 66%
obtained under standard conditions. This suggests that the
radicals are not the only intermediates for benzylmercaptane, and
that the classical anionic pathway[58] can coexist with the former.
Due to these facts, we have focused our attention in the coupling
of thiophenol 4a and alkyne 2a, because it seems that in this case
early stages of the reaction. Interestingly, it is remarkable that
both in presence and in absence of the alkyne, the blue color does
not disappear completely, indicating that the redox reaction is not
complete and that the dimer [Cu(OAc)2]2 is still present in the
mixture. Therefore, both Cu(II) and Cu(I) species are present in
the starting mixture and, in principle, we must consider both of
them as plausible promoters of the coupling. The isolated Cu(I)
complex [CuSPh]n was then subjected to further treatment with 3-
hexyne 2a and either acetic acid (AcOH) or sodium acetate
(NaOAc) under experimental coupling conditions (1:2 molar ratio,
HFIP, 120 °C, 30 min microwave irradiation; equation 3, Chart 3).
This reaction affords 5aa but only in a marginal 12% yield
(compare with 87% yield of 5aa in Chart 2). This result suggests
that Cu(I) species does not promote the formation of 5aa. In the
same way, the reaction of 4a with 3-hexyne 2a and CuI(OAc)
under coupling conditions does not take place at all (equation 4,
Chart 3). These results are good evidences of the role of the
oxidation state of the Cu, pointing to Cu(II) as being the promoter
of the coupling reaction.
We have also examined the source of the PhS moiety. The
reaction of the disulfide PhSSPh with alkyne 2a in the presence
of [Cu(OAc)2]2 under coupling conditions (equation 5, Chart 3)
takes place with formation of 5aa in a moderate 47% yield.
Because it seems that several sources of the PhS unit are
available (PhSH and/or Ph2S2), we have examined the reactivity
of Ph2S2 as source of PhS with two Cu(I) complexes, CuSPh and
CuOAc (equation 6, Chart 3). In both cases, the yields of 5aa are
in the range 0-10%. Clearly this result indicates that, while the
oxidation state of the Cu complex and the ligands around it are
critical, the source of the thiophenolate could be more flexible,
being PhSH the optimal one.
We have also analyzed the different phases of the reaction after
completion, the solid residue and the solution, in order to
determine which is the oxidation state of the Cu at the end of the
reaction. Therefore, once the reaction was finished, the solid
residue was separated by filtration and the solution was
evaporated to dryness, and no further workup was performed.
The two fractions were analysed by XPS, and the results gathered
show that in both cases the Cu present is in oxidation state (+1).
This is based on the position of the Cu2P4/2 and CuLMM bands
and, mainly, on the Auger CuLMM peak (see Supporting
Information for full details). This result allows to discard the
presence of Cu(II) or Cu(0) in the final mixture.
3.- Mechanism determination by DFT methods. With these
data in hand (Cu(II) as starting catalyst, Cu(I) as final species,
PhSH as source of thiolate, radical intermediates), we have
attempted the full determination by DFT methods of the
mechanism of the acetoxythiolation of internal alkynes. We have
selected as model the coupling of 2-butyne 2c with thiophenol 4a
a
single mechanism is taking place. A series of control
experiments, resumed in Chart 3, were conducted using 4a as
substrate.
HFIP
SH
SCu
25 ºC
S
(2)
(3)
(4)
(5)
(6)
+ [Cu(OAc)2]2
+
S
4a
Et
HFIP
120 ºC
AcOH
NaOAc
S
Et
OAc
SCu
+
12% yield
Et
Et
5aa
2a
Et
HFIP
120 ºC
SH
+
+
Cu(OAc)
No reaction
Et
4a
2a
Et
S
Et
[Cu(OAc)2]2
S
+
47% yield
S
S
HFIP
120 ºC
Et
S
OAc
Et
2a
5aa
5aa
CuSPh or
Cu(OAc)
Et
Et
S
+
0-10% yield
OAc
HFIP/AcOH
120 ºC
Et
Et
2a
Chart 3. Experiments for mechanism determination.
and [Cu(OAc)2]2 in HFIP, shown in equation 7.
CH3
When thiophenol 4a, [Cu(OAc)2]2 and 3-hexyne 2a were mixed at
room temperature a clear reaction takes place, from which a pale
yellow solid precipitated. The solid was filtered and identified as
[CuSPh]n, while the disulfide PhSSPh was isolated from the
solution.[59-61] The same result (formation of CuSPh and PhSSPh)
was obtained from the treatment of 4a with [Cu(OAc)2]2 (equation
2, Chart 3), showing that the alkyne does not participate in the
SH
CH3
HFIP
- HOAc
II
I
S
(7)
+
+
+
[Cu (OAc)]2
[Cu (OAc)2]2
OAc
H3C
CH3
4a
2c
5ac
As two nucleophiles are added to the alkyne, two electrons must
be removed at the end of the reaction. Therefore, as in the
oxidative coupling reactions, there is a need for an oxidant to take
these two electrons, keeping the entire process electroneutral.[62]
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Copper(II) acetate has been the most used oxidant in this type of
reactions, but full understanding of its role in the catalytic cycles
is still under discussion.[62] Related with this point, modeling of the
copper(II) acetate reagent deserves some words. In the solid
state it occurs as a dinuclear dihydrate [Cu(OAc)2]2·(H2O)2 with a
paddle-wheel structure.[63] Recent studies by electrospray
ionization mass spectrometry (ESI-MS) of its speciation behavior
in organic solvents as methanol support an extensive aggregation
of Cu(OAc)2 in such media.[64] Accordingly, we have modeled the
implies an energy difference between the open-shell singlet
(OSS) and triplet (T) states of 0.8 kcal mol-1 in favor of the open-
shell singlet.[68] We have considered both electronic states in the
computational study, with no significantly different results
regarding the reactivity. We focus the discussion in the triplet
potential energy surface. OSS results can be found in the
Supporting Information. As the reaction ends up in low spin
products, a change in the spin state occurs. Accurate calculation
of energy splitting between the low-spin and high-spin states is
difficult due to the strong functional dependence it displays.[69-72]
Benchmark calculations of copper reactions involving copper in
different oxidation states have shown that the hybrid TPSSh
functional (10% Hartree-Fock exchange) with the Grimme
dispersion correction, performed best.[73] We have chosen this
functional for the computational study, though other functionals
(B97D, B3LYP-D3, M06 and wB97XD) have been used for
calibration purposes (see Supporting Information).
Cu(II) reagent as
a dimeric [Cu(OAc)2]2·(H2O). The same
description has been employed in a recent theoretical study of
oxidative-coupling reactions.[65] In this way, for every equivalent
of product 5ac formed, two Cu(II) centers are reduced to Cu(I)
along the reaction (equation 7).
Another issue concerns the ground state of [Cu(OAc)2]2 that
exhibits temperature-dependent magnetic behavior. In the solid
state the two unpaired electron spins in the two Cu(II) centers are
antiferromagnetically coupled with J = -296 cm-1.[66,67] That value
Figure 3. Gibbs energy profile at 393.15 K in HFIP solvent for the reaction of 4a with [Cu(OAc)2]2. Energies in kcal mol-1.
3.1.- First Step: S-Coordination-Deprotonation. Control
experiments, described above, demonstrated that the alkyne is
not reacting at the early stages of the reaction. Therefore, we
initially studied the reaction of thiophenol 4a with [Cu(OAc)2]2. The
Gibbs energy profile for this step is depicted in Figure 3. The
reaction begins with the approach of thiophenol to the copper
dimer (structure 1, Figure 3) and the decoordination of one arm of
one bridging acetate (TS_1-2), with the subsequent bonding of
the sulfur atom to one copper center and the orientation of the Ph-
SH proton towards the unbounded oxygen atom of the k1 acetate
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(2). Then, in a practically barrierless process (TS_2-3),[74] the SH
proton is transferred to this acetate, yielding intermediate 3. This
step shows a close relationship with the concerted metalation-
deprotonation process, also called ambiphilic metal−ligand
assistance, extensively discussed for carboxylate-assisted CH
bond activation processes.[75] The main differences with the
reactions involving CH bonds are the involvement of an SH bond,
which rupture is much easier than that of a CH bond, and that the
reaction takes place in the triplet potential energy surface. We
have used a localized orbital approach to analyze the electronic
rearrangements taking place along the reaction mechanism.
Accordingly, Kohn-Sham orbitals are transformed to maximally
localized orbitals and the orbital centroids are used to track the
formation and breakage of bonds and the changes in oxidation
states.[76-78] A full account of the calculations and their outcome is
provided in the Supporting Information. We comment through the
text on three key intermediates (3, 4 and 5brid, Figure 4).
Figure 4. Localized orbital analysis of 3, 4 and 5Sbrid. C atoms are shown as cyan spheres, O in red, S in yellow, H in white, Cu in purple and localized orbital
centroids as small green (for α electrons) and orange (for β ones) spheres. Selected centroids are highlighted (see main text).
Although the coordination-deprotonation of the thiol does not
entail change of the oxidation state in the copper centers and both
Cu ions keep an oxidation state II, a fraction of spin density has
been transferred to the sulfur atom in 3, where the bond between
S and CuA is spin polarized (note the separation of α and β
centroids in Figure 4 and the spin density plot in the Supporting
Information). This polarization is backed by the Mulliken spin
densities, which increase on S (from 0.0 to 0.21) and decrease on
CuA (from 0.59 to 0.50) with respect to the initial adduct 1 (see
Supporting Information). The incipient thiyl radical character of the
sulfur center can account for the formation of the disulfide
PhSSPh that was isolated from the solution when [Cu(OAc)2]2 and
thiophenol 4a were mixed (equation 2). Recent work on
photoinduced, copper-catalyzed C-S cross-couplings with aryl
halides highlighted the significant radical character of the sulfur
center of thiolate ligands in copper(II)-thiolate complexes.[79,80]
Intermediate 3 will be the active species that reacts with the
alkyne in the following step. Whatever the functional employed, it
is formed with a low barrier (13.4 kcal mol-1 at the TPSSh-D3/BS2
level). This step is slightly endergonic, with the formed
intermediate 3 lying 5.5 kcal mol-1 above the separated reactants
(Figure 3).
documented feature,[81,82] the reactivity of a metal-stabilized thiyl
radical with an unsaturated fragment is much less common.[83-86]
3·alkyne is the Wan der Waals complex formed between 3 and
the alkyne (the shortest Cu-Calkyne and S-Calkyne distances are 3.20
and 4.0 Å, respectively). This intermediate is taken as origin of
energy in the S- and O-addition to alkyne reactions (Figures 5, 6).
Due to the entropic penalty, probably overestimated,[87] it lies 6.1
kcal mol-1 above the separated reactants. Approaching the alkyne
to the sulfur center induces significant changes in the electron
distribution of the system. After crossing transition state TS_3-4,
a C-S bond is formed (intermediate 4). In 4, the S–C bond is
formed by an α electron from S and a β electron from a π orbital
of the C–C triple bond (see α and β centroids shared by the two
atoms along the S–C axis, Figure 4). Consequently, an α electron
is left on the other C of the multiple (now double) bond, in
accordance with a vinyl radical character of this intermediate. The
S–CuA bond is no longer spin polarized, having CuA received a β
electron and thus been reduced to Cu(I). CuB remains in oxidation
state II (see spin density plot and localized orbital analysis in the
Supporting Information). The process may be formally seen as a
single electron-transfer (SET) process, in which CuA oxidizes the
alkyne to form a carbon radical. However, the process takes place
intramolecularly within the organometallic complex, whereas SET
processes are often understood to take place intermolecularly.
Furthermore, the C radical is generated via a rearrangement of
the electron pairing around the S atom, as highlighted by the
3.2.- Second Step: C-S Coupling. The second step involves the
formation of the S-C bond, by attack of the Cu-stabilized S-
centered incipient thiyl radical in 3 to the alkyne 2c. While the
attack of a free S-centered radical to an alkyne is a well-
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10.1002/chem.201802546
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localized orbital analysis, rather than a long-range electron
transfer. Because of these reasons, we prefer not to use the SET
terminology to describe this pathway. The S-addition entails a
rather high Gibbs-energy barrier (27.7 kcal mol-1 at the TPSSh-
D3/BS2 level), yet readily accessible under the experimental
conditions (T = 120 °C).
The process described above can be related with the metal-free
radical addition of thiols to alkynes, named, by analogy with the
‘ene’-counterpart, ‘thiol–yne coupling’ (TYC).[81,82] In this organic
reaction a sulfanyl radical (RS·) is initially created in the presence
of radical sources (peroxides, irradiation with UV light). Then, this
sulfanyl radical adds to the carbon–carbon multiple bond to afford
a β-sulfanyl-substituted vinyl radical; subsequently, in a radical
chain mechanism, hydrogen transfer from the starting thiol affords
a vinyl sulfide and a new sulfanyl radical that sustains the chain.
The whole process, although regioselective, at least with terminal
alkynes, is usually scarcely stereoselective, since the vinyl sulfide
products are often formed as mixtures of both E- and Z-
stereoisomers.[88,89]
create a Cu-C bond (intermediate 5T), losing its character of vinyl
radical and placing the Cu-bonded carbon atom in the right
position to be attacked by an acetate ligand in the next step. In 5T
the Cu2 core has returned to a CuII-CuII oxidation sate. At this point
a crossing from the triplet to the singlet potential energy surfaces
takes place easily (from 5T to 5S). In 5S, the system is not spin
polarized (singlet state). Interestingly, compared to 4, the
oxidation state of the copper ions has changed, from CuA(I),
CuB(II) in 4 to CuA(III), CuB(I) in 5S (see Supporting Information).
The geometries at the metal centers (CuA: square planar, CuB:
tetrahedral) are consistent with this assignment. Passing from 5T
to 5S implies the CuII disproportionation to CuI and CuIII.[90,91] In the
past few years CuIII species have gained relevance as important
intermediates in copper-catalyzed reactions.[91]
3.- Third Step: C-O Coupling. The C-O bond is formed in the
last step, which entails the addition of an acetate ligand to the
carbon center. It takes place in the singlet potential energy
surface, starting from 5S (Figure 6).[92] The stereoselectivity of the
final alkene is decided in this step.
In 4 the S-C coupling has already taken place. 4 reorganizes with
a very low barrier (3.8 kcal mol-1 at the TPSSh-D3/BS2 level) to
Figure 5. Gibbs energy profile at 393.15 K in HFIP solvent for the S-C coupling step. Energies in kcal mol-1.
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10.1002/chem.201802546
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Figure 6. Gibbs energy profile at 393.15 K in HFIP solvent for the C-O coupling step. Energies in kcal mol-1
Direct attack of a monodentate acetate ligand of 5S in cis with
respect the vinyl group produces the C-O coupling with a Gibbs
energy barrier of 16.5 kcal mol-1 with respect 5S (TS_5S-6cis,
Figure 6). In this process, the CuA(III) center in 5S becomes a
copper(I) center in the product 6-cis. However, this mode of
attack yields the (Z)-isomer of the olefin, which is not
experimentally observed. All the attempts we have done to obtain
the (E)-isomer directly from 5S has been unsuccessful. We have
also considered a trans addition to the alkyne by going via h2-vinyl
pathway, as originally proposed for trans hydrosilylation,[93] but we
have not been able to find such a h2-vinyl intermediate in this
system. All the optimizations starting from such structure revert to
the initial h1-vinyl-copper intermediate 5S. Exploring alternative
routes for the trans addition, we found that the flexibility of the
dicopper-acetate scaffold allows a very easy rearrangement
(through TS_5S’-5Sbrid, Figure 6) of the vinyl ligand, passing from
a terminal to a bridging coordination, in which the vinyl ligand is
bonded to both copper centers (5Sbrid). The structure of 5Sbrid has
a s,p-vinyl ligand: the C=C unit is bonded to one copper center
From this intermediate the trans addition takes place, with a lower
barrier (15.8 kcal mol-1 from 5S’, TS_5Sbrid-6trans, Figure 6) and
yields a slightly more stable product (6trans). Analysis of the
electron rearrangements in this step, by following the
displacement of the centroids of localized orbitals (in the
Supporting Information), reveals that one O-electron pair of the
acetate bonded to CuB attacks the carbon atom h2-coordinated to
CuB and which forms the s(Cu-C) with CuA. At the same time that
the C-O bond is being formed, the s(Cu-C) bond is breaking, and
this bonding electron pair is being transferred to the CuA. In this
way, CuA is reduced from +3 to +1 oxidation state and two Cu(I)
centers are present in 6trans. Overall, the two Cu(II) centers of
the reagent have accepted the two electrons released in the
acetoxythiolation process.
As acetate anions may be present in the reaction medium, we
have also considered the possibility that the trans attack occurs
from an external non-bonded AcO- (see Supporting Information).
This reaction has a slightly higher barrier (16.3 kcal mol-1) than
that from the coordinated acetate (15.8 kcal mol.1 TS_5-6trans)
,
(CuA) by a s(Cu-C) bond and by a p(C=C)-Cu to CuB. In this sense, but still lower than the cis attack.
it is reminiscent of the proposed h2-pathway.[93] In 5Sbrid CuA and
CuB keep their +3 and +1 oxidation states, respectively (Figure 4).
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10.1002/chem.201802546
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performed using column chromatography on SiO2 and Et2O/hexane 5:95
to 25:75 as eluents.
Conclusions
The work here reported achieves the synthesis of tetrasubstituted
olefins from reaction of benzylmercaptanes or thiophenols with
internal alkynes promoted by [Cu(OAc)2]2, in such a way that one
sulfide fragment and one acetate group are incorporated to the
alkyne skeleton. This method presents some remarkable features,
namely: (a) the selectivity displayed by the process, because only
the cross-coupling product is formed: the products from bis-
thiolation, bis-acetoxylation or the thiol-yne derivatives were not
observed at all. In addition, (b) the stereoselectivity of the process
is complete, since only the (E)-isomer of the olefin is formed; and
(c) high levels of regioselectivity are also achieved when
asymmetrical alkynes are used. Additional features are (d) its
versatility, since a wide array of substituents in the alkyne and the
thiolate are tolerated; (e) its simplicity, because the substrates do
not need previous transformations nor activations with specific
reagents; (f) the type of products resulting from the reaction, since
they contain two good leaving groups and an orthogonal reactivity
is easily envisaged; and (g) the whole process is mediated by
[Cu(OAc)2]2, a simple complex with an earth-abundant metal,
cheap, showing a low toxicity and high sustainability. DFT
calculations underline the key role of the dimeric copper(II)
diacetate in the process. It confers the thiyl radical character to
the Cu-coordinated thiol, generating the active species 3.
Moreover, by means of a sequence of changes of the oxidation
states of the two copper centers accepts the two electrons
released in the addition of two nucleophiles to the alkyne.
Computational Details. Density functional theory (DFT) calculations were
performed with the TPSSh density functional,[94,95] supplemented with the
Grimme’s dispersion correction D3.[96] This functional accurately
reproduces the relative energies of spin sates of first-row transition metal
complexes,[97] and predicts reactivity at CuIII.[73] Additional calibration
calculations were carried out with the B97D, B3LYP-D3, wB97XD and M06
functionals (Supporting Information). All intermediates and transition
states were fully optimized in hexafluoroisopropanol solution (HFIP, e =
16.7) using the continuum method SMD.[98] Gibbs energies in HFIP were
calculated at 393.15 K. All energy values reported in the main text
correspond to Gibbs energies in HFIP in kcal mol−1. See Supporting
Information for further details on the calculations
Characterization of tetrasubstituted olefins. Selected examples are
shown here. For full details, see Supporting Information.
3ab: Colourless oil (214 mg, 71%). 1H NMR (CD2Cl2, 300.13 MHz, r.t.) dH:
1.22 (s, 9H, CMe3), 2.17 (s, 3H, C(O)Me), 2.22 (s, 3H, =CMe), 3.85 (s, 2H,
CH2S), 7.3-7.5 (m, 5H, Ph). 13C{1H} NMR (CD2Cl2, 75.47 MHz, r.t.) dC: 20.7,
21.3, 30.4, 37.9, 41.1, 127.0, 128.4, 129.1, 130.7, 138.2, 151.4, 168.7.
(ESI)+ m/z: [M+K]+ (100) 317. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C16H22NaO2S 301.1238, obtained 301.1223.
3ac: Colourless oil (177 mg, 75%). 1H NMR (CDCl3, 300.13 MHz, r.t.) dH:
1.86 (q, 3H, 5JHH = 1.5 Hz, =CMe), 1.93 (q, 3H, 5JHH = 1.5 Hz, =CMe), 2.15
(s, 3H, C(O)Me), 3.84 (s, 2H, CH2S), 7.2-7.4 (m, 5H, Ph). 13C{1H} NMR
(CDCl3, 75.47 MHz, r.t.) dC: 17.6, 20.7, 37.1, 117.5, 127.0, 128.4, 128.8,
138.3, 148.6, 168.3. (ESI)+ m/z: [M+K]+ (100) 275. HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C13H16NaO2S 259.0769, obtained 259.0777.
5aa: Colourless oil (217 mg, 87%). 1H NMR (CD2Cl2, 300.13 MHz, r.t.) dH:
Experimental Section
3
0.89 (t, 3H, JHH = 7.6 Hz, CH2CH3), 0.94 (t, 3H, 3JHH = 7.6 Hz, CH2CH3),
3
2.02 (q, 2H, JHH = 7.2 Hz, CH2CH3), 2.11 (s, 3H, C(O)Me), 2.55 (q, 2H,
General Remarks. The reactions were performed without special
precautions to exclude air and/or moisture. The solvents were of
commercial grade and used as received. All reactions were carried out
under microwave heating on a CEMTM S-class Microwave Synthesis
System, at 120 °C (150 W). Flash column liquid chromatographies were
performed on aluminium oxide 90 neutral (50-200 µm). Infrared spectra
(4000-380 cm-1) were recorded on a Perkin-Elmer Spectrum One IR
spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3
solutions at 25 °C on Bruker AV300 spectrometers (d in ppm, J in Hz) at
1H operating frequency of 300.13 MHz. 1H and 13C spectra were
referenced using the solvent signal as internal standard. ESI (ESI+) mass
spectra were recorded using an Esquire 3000 ion-trap mass spectrometer
(Bruker Daltonic GmbH) equipped with a standard ESI/APCI source.
Samples were introduced by direct infusion with a syringe pump. Nitrogen
served both as the nebulizer gas and the dry gas. HRMS and ESI (ESI+)
mass spectra were recorded using an MicroToF Q, API-Q-ToF ESI with a
mass range from 20 to 3000 m/z and mass resolution 15000 (FWHM). X-
ray photoelectron spectroscopy (XPS) was carried out on an ESCAPlus
Omicron spectrometer using a monochromatized Mg X-ray source (1253.6
eV). Data were analyzed using Casa XPS software package.
3JHH = 7.3 Hz, CH2CH3), 7.0-7.1 (m, 1H, SPh), 7.2-7.4 (m, 4H, SPh).
13C{1H} NMR (CD2Cl2, 75.47 MHz, r.t.) dC: 11.8, 12.7, 20.8, 24.6, 25.4,
123.0, 126.0, 128.2, 129.3, 136.2, 155.8, 169.1. (ESI)+ m/z: [M+K]+ (100)
289. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C14H18NaO2S 273.0925,
obtained 273.0921.
5ab: Yellow oil (195 mg, 74%). 1H NMR (CD2Cl2, 300.13 MHz, r.t.) dH: 1.24
(s, 9H, CMe3), 2.19 (s, 3H, =CMe), 2.22 (s, 3H, C(O)Me), 7.0-7.1 (m, 1H,
SPh), 7.2-7.4 (m, 4H, SPh). 13C{1H} NMR (CD2Cl2, 75.47 MHz, r.t.) dC: 20.8,
21.1, 30.1, 38.1, 124.7, 125.7, 127.8, 128.9, 137.7, 153.3, 168.8. (ESI)+
m/z: [M+K]+ (70) 303. HRMS (ESI-TOF) m/z: [M-H+H2O]+ calcd for
C15H21O3S 281.1211, obtained 281.1201.
5ac: Yellow oil (198 mg, 89%). 1H NMR (CD2Cl2, 300.13 MHz, r.t.) dH: 1.71
(q, 3H, 3JHH = 1.5 Hz, =C-Me), 2.07 (q, 3H, 3JHH = 1.5 Hz, =C-Me), 2.09 (s,
3H, C(O)Me), 7.0-7.1 (m, 1H, SPh), 7.2-7.4 (m, 4H, SPh). 13C{1H} NMR
(CD2Cl2, 75.47 MHz, r.t.) dC: 17.9, 18.1, 20.9, 117.3, 126.3, 128.7, 129.4,
135.5, 150.9, 168.7. (ESI)+ m/z: [M+K]+ (100) 261. HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C12H14NaO2S 245.0612, obtained 245.0619.
General experimental procedure for the synthesis of tetrasubstituted
olefins: To a solution of the thiol 1a-1e or 4a-4g (1 mmol) and the
corresponding alkyne 2a-2e (2 mmol) in HFIP (4 mL), [Cu(OAc)2]2 (181 mg,
0.5 mmol) was added. The reaction mixture was heated in a microwave
reactor at 120 °C for 30 min. After that, the solvent was removed to dryness
and the solid residue was purified by flushed column chromatography in
neutral alumina using dichloromethane as eluent. Further purification was
Acknowledgements
Funding by the MINECO (Spain, Project CTQ2017-87889-P) and
Gobierno de Aragón (Spain, research group: Activación
Molecular a través de Organometálicos, E97) is gratefully
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Entry for the Table of Contents
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Pedro Villuendas, Sara Ruiz, Pietro
Vidossich, Agustí Lledós* and Esteban
P. Urriolabeitia*
Page No. – Page No.
Synthesis of tetrasubstituted olefins
by Cu-mediated acetoxythiolation of
internal alkynes: scope and
mechanistic studies
The Cu-mediated synthesis of tetrasubstituted E-olefins by stereo- and
regioselective addition of an acetate group and a thiolate to an unactivated internal
alkyne is described. The mechanism has been determined by DFT methods and
shows that it takes place through Cu-stabilized radical intermediates.
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