Intertwined Analytical, Experimental and Theoretical Studies on the Formation and Structure of a Copper Dienolate

Article abstract of DOI:10.1002/chem.202100596

The reaction of a silyl dienolate, a Cu(II) salt and TBAT yielding the corresponding copper dienolate is addressed. A combined NMR and cyclic voltammetry analysis first highlight the role of TBAT in the Cu(II) to Cu(I) reduction and the structure of the precatalytic species. From these first results a second set of NMR and theoretical studies enable the determination of the structure and the mechanism of formation of the copper dienolate catalytic species. Finally, we showed that that the copper catalyst promote the E/Z s-cis/s-trans equilibration of the silyl dienolate precursor through a copper dienolate intermediate. All of these results unveil some peculiarities of the catalytic and asymmetric vinylogous Mukaiyama reaction.

Full text of DOI:10.1002/chem.202100596

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Intertwined Analytical, Experimental and Theoretical
Studies on the Formation and Structure of a Copper
Dienolate
Baptiste Lecachey,[b] Laetitia Palais,[c] Benoît de Courcy,[a] Samira Bouauli,[a]
Muriel Durandetti,*[c] Hassan Oulyadi,*[c] Anne Harisson-Marchand,[c] Jacques Maddaluno,[c]
Hélène Gérard,*[a] Emmanuel Vrancken,*[b] and Jean-Marc Campagne*[b]
Abstract: The reaction of a silyl dienolate, a Cu(II) salt and
TBAT yielding the corresponding copper dienolate is ad-
dressed. A combined NMR and cyclic voltammetry analysis
first highlight the role of TBAT in the Cu(II) to Cu(I) reduction
and the structure of the precatalytic species. From these first
results a second set of NMR and theoretical studies enable
the determination of the structure and the mechanism of
formation of the copper dienolate catalytic species. Finally,
we showed that that the copper catalyst promote the E/Z s-
cis/s-trans equilibration of the silyl dienolate precursor
through a copper dienolate intermediate. All of these results
unveil some peculiarities of the catalytic and asymmetric
vinylogous Mukaiyama reaction.
Introduction
synthetic applications such as copper catalyzed reductive-,[1]
Mukaiyama-,[2] alkylative-,[3] borylative-,[4] direct- aldol or Man-
nich or Michael type reactions,[5] little is known about their
structure, and the mechanisms of these processes are, to the
best of our knowledge, not fully described and understood.
Among these reactions, we became interested in the develop-
ment of copper-catalyzed catalytic and asymmetric vinylogous
Mukaiyama reactions leading to enantioenriched lactones 2
starting from silyldienolate 1. Indeed, this methodology proved
to be a powerful synthetic tool applied in the total synthesis of
natural products (Scheme 1).[6,7]
The catalytic system (Cu(OTf)2, (S)-tolBINAP, TBAT) used in
these reactions was originally developed by Carreira in the first
enantioselective vinylogous Mukaiyama reaction based on the
activation of the cyclic silyl dienolate 3 (Scheme 2).[8,9]
An IR study by Carreira suggested the formation of a Cu(I)
dienolate intermediate 4 as a possible reactive species but the
exact structure of which was unknown (Scheme 2).[9] In our own
workwe used linear silyl dienolates 1a,b that could give rise to
a complex mixture of Cu(I) dienolate species 5–7 (Scheme 3).[6]
Therefore the reactivity could result from an allyl copper or a
copper enolate reagent due to the possible metallotropic
equilibria between O-metalated and C-metalated (α and γ)
forms.[10]
For many years, the real structure of organometallic species in
solution has remained unknown thus limiting a fine compre-
hension of reaction mechanisms. Cutting-edge analytical and
DFT techniques could lift a corner of the veil and thus pave the
way for new synthetic developments.
Organometallic reagents can be roughly divided in two
major classes whether they are subjected or not to metal-
lotropic equilibrium. Due to possible multiple aggregation
states and equilibrium between them, the structural determi-
nation of organometallic reagents without metallotropic equili-
brium is in itself challenging. For organometallics subject to
metallotropic equilibrium, the situation is even more complex.
Copper enolates, a popular class of organometallic reagents
due to their polyfunctionality, belong to this last category.
Although copper enolates are commonly used in various
[a] Dr. B. de Courcy, Dr. S. Bouauli, Prof. H. Gérard
Sorbonne Université, CNRS, Laboratoire de Chimie Théorique, LCT
75005 Paris (France)
E-mail: helene.gerard@upmc.fr
[b] Dr. B. Lecachey, Dr. E. Vrancken, Prof. J.-M. Campagne
ICGM, Univ. Montpellier, CNRS, ENSCM
Montpellier (France)
With the aim to understand the peculiarities of this trans-
formation and to extend its synthetic scope, we were keen to
unveil the mechanism of formation of the reactive species and
to determine their real structures in solution. We thus under-
took intertwined experimental, analytical and DFT studies in
order to determine i) the nature of the precatalytic species
formed from the catalytic system (Cu(OTf)2, (S)-tolBINAP, TBAT)
ii) the nature of the catalytic species obtained through reaction
of these precatalytic species with silyl dienolate 1a,b.
E-mail: emmanuel.vrancken@enscm.fr
jean-marc.campagne@enscm.fr
[c] Dr. L. Palais, Dr. M. Durandetti, Prof. H. Oulyadi, Dr. A. Harisson-Marchand,
Dr. J. Maddaluno
Normandie Univ., UNIROUEN, INSA Rouen, CNRS, Laboratoire COBRA (UMR
6014 & FR 3038)
76000 Rouen (France)
E-mail: muriel.durandetti@univ-rouen.fr
hassan.oulyadi@univ-rouen.fr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100596
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Table 1. Influence of copper salts on the vinylogous Mukaiyama reaction leading to lactone 2a.
Entry
CuX
Copper/TBAT ratio
Conversion %[a]
1
2
3
CuII(OTf)2
1:2
1:1
1:1
>90%
No reaction
>90%
CuII(OTf)2
(CuIOTf)2·C6H6
[a] Based on silylated dienolate 1a+1b.
Results and Discussion
Determination of precatalytic species formed from the
catalytic system
Experimentally, the standard reaction conditions are: a solution
of Cu(OTf)2 (10 mol%) and (S)-tolBINAP (10 mol%) in anhydrous
THF is stirred from 30 minutes at room temperature (rt, a clear
yellow solution was obtained).[6c,f] A solution of ((n-Bu4N)Ph3SiF2
(TBAT), 20 mol%, 2 equivalents compared to copper) in anhy-
drous THF is then added and, after an additional 15 minutes at
this temperature, a bright yellow solution is obtained. The
mixture of silyl dienolates 1a,b (71:29, 1.5 equivalent) is added
dropwise (the solution turned red brown in color) followed by
the aldehyde (1 equiv.) and the resulting mixture is stirred
overnight at rt. Although the copper precatalytic species was
initially described as a “CuF2(tol-BINAP)” complex by Carreira,[8]
further studies suggested the formation of a copper(I) complex
“CuF(tolBINAP)”. Based on Carreira’s hypothesis, a possible Cu(II)
to Cu(I) reduction pathway could imply the oxidative coupling
of the enolate moiety or phosphine oxidation.[9] However this
mechanistic scenario does not explain the need of two equiva-
lents of TBAT per Cu(II) salt. Indeed, no product was formed
when we performed the vinylogous Mukaiyama reaction in the
presence of 1 equivalent of TBAT (table 1, compare entries 1
and 2). Interestingly, the reaction proceeds efficiently in the
presence of 1 equivalent of TBAT using a Cu(I) salt (CuIOTf)2
instead of CuII(OTf)2 (table 1, entry 3). This result suggests that
the TBAT could be implied in the reduction process and that in
these reaction conditions BINAP is not able to reduce the Cu(II)
salt at rt.[11]
Scheme 1. Catalytic and asymmetric vinylogous Mukaiyama reactions for the
synthesis of enantioenriched lactones 2 and applications in natural product
synthesis.
This hypothesis prompted us to undertake coupled NMR
and cyclic voltammetry (CV) studies in order to monitor
changes in copper complex leading to the formation of the
precatalyst species. These analysis were sequentially carried out
at three different stages; i) the 1:1 mixture of Cu(OTf)2 and
BINAP, then ii) the addition of one equivalent of TBAT and
finally iii) the addition of a second equivalent of TBAT:
Scheme 2. Carreira’s catalytic and asymmetric vinylogous Mukaiyama
(CVAM) reaction.
Stage 1 : CuIIðOTfÞ2 þ BINAP ! C1
Stage 2 : C1 þ TBAT ! C2
Scheme 3. Possible metallotropic equilibrium between O-metalated and C-
metalated forms.
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broad signal at À 54.0 ppm is observed for CuII(OTf)2. The signal
Stage 3 : C2 þ TBAT ! C3
becomes thinner and is shielded as the amount of BINAP is
increased. At a 1:1 ratio, a signal at À 77.4 ppm is observed (See
Supporting Information Figure E for details). Interestingly, no
signal of ’free’ CuII(OTf)2 could be observed even for the use of
Our aim is thus to determine the nature of C1 to C3
complexes. Since the fluorine atom seems to be closely
associated to the catalyst, NMR studies focused on this nucleus.
The reaction conditions were thus reproduced in an NMR tube
and monitored by 19F NMR experiments, and CV studies were
conducted simultaneously (Figure 1). Indeed CV is also a useful
analytical technique to obtain mechanistic information, taking
advantage that the oxidation or reduction currents are propor-
tional to the concentration of electroactive species to examine
directly the oxidation degree of the Cu atom. Furthermore, CV
enables to study highly reactive species (short-lived species), as
they appear stable at the time of the cyclic voltammetry.[12] The
electrochemical behavior of Cu(I) or Cu(II) in the presence of
chelating ligands is well documented, but generally with
diimine ligand such as bipyridine or phenanthroline, and more
specifically for the oxidation of Cu(I) to Cu(II).[13] Some papers
reported organic phosphines as well as their bidentate deriva-
tives as ligand of copper, but the majority of these studies deal
with mixed-ligand complexes, those contain phenylphosphine
only as spectator and the cathodic behavior of Cu(I) complexes
generally shows a ligand-centered reduction, the Cu(0) forma-
tion being not visible.[14] Finally few works concerning copper
BINAP complexes are reported,[15] and no on electrochemistry.
The overall results of stages 1 to 3 are reported in Figures 1
(NMR) and 2–4 (CV).
sub-stoichiometric amount of BINAP, suggesting
a rapid
exchange between Cu(II) and BINAP (See Supporting Informa-
tion Figure E). In a second set of experiments, CV were carried
out on a 0.1 M solution of n-Bu4NBF4 used as supporting
electrolyte in THF at room temperature. The electrochemical
behavior of Cu(II) was studied at a scan rate of 500 mV.sÀ 1 by
addition of CuII(OTf)2 (10 mM). Initially, an irreversible reduction
peak R1 was detected at À 0.05 V/SCE (see Supporting Informa-
tion, Figure C). After addition of BINAP (10 mM), R1 disappeared
and a new reduction peak R2 developed at À 1.25 V/SCE
(Figure 2a), attesting the complexation of Cu(II) by BINAP. This
non-reversible signal, assigned to the reduction of Cu(II) into
Cu(0), both coordinated to the ligand BINAP, is relatively large
because of the presence of different complexes in equilibrium
in solution that can be reduced at very close potentials. The
presence of one equivalent of BINAP generates a new system R3
at À 2.1 V/SCE. This peak can be attributed to the reduction
process of BINAP into BINAP·À associated to Cu(0). It must be
pointed out that BINAP was not found to be reducible in a
separate experiment performed under the same conditions (See
Supporting Information Figure D).
In order to compare Cu(II) and Cu(I), and thus to make sure
that no reduction of Cu(II) had taken place through addition of
BINAP, we have studied by CV the electrochemical behavior of
(CuIOTf)2 ·C6H6 in the presence of BINAP (Figure 2b) in the same
experimental conditions. We note that the presence of BINAP
leads to the disappearance of the reduction of Cu(I) at À 0.35 V/
SCE (see Supporting Information) and the emergence of a new
electrochemical system at À 1.04 V/SCE. If we compare the two
curves obtained with Cu(I) and Cu(II), we can notice a few
difference in the electrochemical behavior: the signal observed
at À 1.25 V/SCE in the case of “Cu(II)·BINAP” is shifted towards
the less negative potentials (centered at À 1.04 V/SCE) and is
twice smaller, which is consistent with a one electron reduction
compared to the two electron system involved with Cu(II). The
peak at À 2.1 V/SCE attributed to the reduction process of BINAP
into BINAP·À associated to zero-valent copper is still present.
Stage 1: Cu(OTf)2 +BINAP
At first, the 19F NMR spectra of CuII(OTf)2 was recorded in
anhydrous THF-d8 at room temperature with increasing
amounts of rac-BINAP (ie Cu:BINAP=1:0.25; 1:0.5; 1:1). A
Figure 1. 19F NMR spectra (470 MHz, THF-d8, 298 K) of solution of: (1) Cu(OTf)2
(blue spectrum); (2) Cu(OTf)2 +BINAP (black spectrum); (3) Cu(OTf)2 +BINAP
+1eq TBAT (red spectrum) (4) Cu(OTf)2 +BINAP+2eq TBAT (green spec-
trum).
Figure 2. Cyclic Voltammograms in THF+0.1 M NBu4BF4, at a gold disc
microelectrode (0.25 mm diameter) at v=0.5 V.sÀ 1 and at r.t. Left) 10À 2
M
Cu(OTf)2 +1 molar equiv. of BINAP (blue curve); right) 10À 2 M CuOTf+1
molar equiv. of BINAP (pink curve).
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Stage 2: Addition of the first equivalent of TBAT
This point was also examined through CV. After addition of
a second equivalent of TBAT, the reduction peak of Cu(I) at
À 1.04 V/SCE disappeared totally, and a new reversible system
appeared at À 1.9 V/SCE (Figure 3c). This was also observed
when introducing only one equivalent of TBAT in a “Cu-
(I)·BINAP” solution. According to these observations, this new
system can be attributed to the reduction of the “CuF·BINAP”
complex, which is the precatalyst during the CAVM process.
These characteristic reduction steps are summarized in
Scheme 4.
The addition of one equivalent of TBAT in a solution containing
“Cu(II)·BINAP” complex leads to the formation of a copper
species that is reducible at À 1.04 V/SCE that is similar to the
reduction potential of “Cu(I)·BINAP” observed above (Figure 2b,
Figure 3a-b and Figure 4). It is thus possible to assume that
TBAT induces the reduction of “Cu(II)·BINAP” into “Cu(I)·BINAP”.
The 19F NMR spectra of the 1:1 mixture of Cu(OTf)2 ·BINAP
and TBAT shows a lack of a broad peak at À 77 ppm and the
appearance of two new peaks at À 78 and À 170 ppm. The first
one was attributed to the overlay of the OTf signals in n-
The above observations (experimental, 19F NMR and CV) are
in good accordance with Carreira’s hypothesis of “CuF·tolBI-
NAP” as the relevant precatalyst.[9] Furthermore, all these
experimental evidences show that TBAT (2 equivalents per
copper) has two distinct roles: the reduction of Cu(II) in Cu(I)
and the formation of the active “CuF·diphosphine” precatalyst.
Nature of the catalytic species obtained through reaction of
these precatalytic species with silyldienolates
The next step of our study deals with the reactivity of the
above identified precatalyst with the silyldienolates 1a,b (see
Scheme 3). This study was carried coupling multinuclear NMR
studies and computational investigations.
Bu4NOTf and in CuIOTf·BINAP. Indeed the comparison of the 19
F
NMR spectra of nBu4NOTf (generated from TBAF and TMSOTf),
and the copper salt obtained by the mixture of one equivalent
of (CuIOTf)2 ·C6H6 with two equivalents of BINAP shows that
these two species have the same chemical shift (See Supporting
Information). The second one was attributed to Ph3SiF by
comparison with an authentic sample (See Supporting Informa-
tion).
Stage 3: Addition of the second equivalent of TBAT
When the 71:29 E:Z mixture of silyldienolates 1a,b was
added to the CuII(OTf)2 / BINAP / TBAT (2 equiv) mixture, the
À 138 ppm signal disappeared with the concomitant apparition
of a signal at À 158 ppm that corresponds to TMSF (attributed
by comparison with an authentic sample, see Figure 5). As
previously suggested by control experimental results (see
table 1 and stage 2) this confirm that the Cu(II) complex is
reduced to Cu(I) in the presence of TBAT. This can be associated
to a dienolate chain transfer step to the Cu(I), associated to an
exchange with F and thus further confirms that the À 138 ppm
signal corresponds to a “CuF” species.
When one more equivalent of TBAT is added to the 1:1:1
mixture of CuII(OTf)2, BINAP and TBAT, the “CuIOTf·BINAP” 19F
NMR signal disappear and a new signal can be observed at
À 138 ppm. This signal was attributed to “CuF·BINAP”.[16] Indeed,
I
*
when mixing half an equivalent of (CuOTf)2 C6H6 complex with
one equivalents of BINAP and one equivalent of TBAT, the same
signal could be observed at À 138 ppm (along with Ph3SiF and
n-Bu4NOTf signals, see Supporting Information).
This TMS/F exchange step has extensively been studied
computationally by some of us recently, using [Cu(PH3)2]+ as a
model copper complex.[17] We demonstrated that the exchange
between F and a highly conjugated enolate chain like the one
used here is highly exergonic and irreversible. The same
mechanism was recomputed here, using a “small model” of the
Cu(I)·tolBINAP to replace the Cu(I)·(PH3)2 complex used
previously (see computational details) and a non-substituted
silyl dienolate SE (see Table 2).[18] Similar results are obtained,
with a Gibbs free energy of activation of 13.8 kcalmolÀ 1 for
Figure 3. Cyclic Voltammograms in THF+0.1 M NBu4BF4, at a gold disc
microelectrode (0.25 mm diameter) at v=0.5 V.sÀ 1 and at r.t. Blue curve)
10À 2 M Cu(OTf)2 +1 molar equiv. of BINAP ; green curve)+1 molar equiv.
TBAT; red curve)+2 molar equiv. TBAT.
enolate
/
F
exchange (TS1) and an exergonicity of
12.2 kcalmolÀ 1 (P1). Nevertheless, an additional reaction path
Figure 4. Cyclic Voltammograms in THF+0.1 M NBu4BF4, at a gold disc
microelectrode (0.25 mm diameter) at v=0.5 V.sÀ 1 and at r.t. Green curve)
10À 2 M Cu(OTf)2 +1 molar equiv. of BINAP+1 molar equiv. TBAT; pink curve)
10À 2 M CuOTf+1 molar equiv. of BINAP.
Scheme 4. Reduction of Cu(I) and (II) in presence of BINAP and TBAT.
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free energy data are gathered in Table 2. Although we had
expected significant differences, it appears that all pathways are
close in energy. Whatever the pathway at stake, these results
confirm that the precatalyst is converted in an irreversible
manner to a copper dienolate complex P1-4 in presence of the
silyldienolate SE.
The structure determination of these various Cu-dienolate
reagents CD1-4 was next attempted using NMR {1H, 13C}
spectroscopy. However, in the real reaction conditions
(10 mol% of copper), the organocopper species are obtained in
a too small concentration to enable their direct observation.
The structures were thus sampled more closely through DFT
computations.
The computational studies were first carried out using the
simplified model described in table 2. More than 20 different
structures could be obtained, depending on conformations and
side coordination. The obtained structures can be classified
among four categories analogous to the Cu dienolates products
described in Table 2 that mainly differ by the s-cis or s-trans
conformation of the ester moiety.[20] The most stable structures
in each category were then recomputed using a complete
model including the full tolBINAP ligand and the γ-substituted
copper dienolate. They correspond to two CuÀ O enolates
(CD1m and CD2m) and two CuÀ C enolates (CD3m and CD4m).
The three most stable structures CD2m-4m shown in Figure 6
all lie within 5 kcalmolÀ 1. The trans dienolate are found in CuÀ O
Figure 5. Study of the formation of the CuI dienolate reagent: 19F NMR
spectra (470 MHz, THF-d8, 298 K) of mixture of (1) Cu(OTf)2 +BINAP+2TBAT
(green spectrum); (2) Cu(OTf)2 +BINAP+2TBAT+1a,b (black spectrum);
(3) Me3SiF (red spectrum) and (4) TMSOTf+TBAT (blue spectrum).
could be located, that takes advantage of the formation of π-
adduct A3 and A4 between the [Cu]-F precatalytic species and
the terminal C=C double bond to directly yield C-bonded
copper dienolates CD3.[19] Reaction pathways yielding to CuÀ C-
and CuÀ O-dienolates both in s-cis and s-trans arrangement
around the C2–C3 bond CD1-4 were localized, and their Gibbs
Table 2. Energies/Gibbs Free energy with respect to the most stable silyldienolate SE (s-trans) in kcal molÀ 1
.
Entry
Adduct
TS
Products
1
2
3
4
A1: À 8.3/3.4
A2: À 6.1/6.3
A3: À 12.1/1.2
A4: À 8.9/4.9
TS1: À 0.4/13.8
TS2: 1.0/15.1
CuÀ O-dienolate s-trans CD1
CuÀ O-dienolate s-cis CD2
CuÀ C-dienolate s-trans CD3
CuÀ C-dienolate s-cis CD4
À 12.4/À 12.2
À 18.0/À 17.9
À 17.6/À 16.3
À 18.0/À 17.8
TS3: À 1.2/13.4
TS4: À 2.1/13.1
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and CuÀ C form, but the CuÀ O structure CD1m is high in energy
compared to CD2m-4m. The C-copper dienolates CD3m and
CD4m exhibit a η3 terminal coordination, whatever the s-trans
or s-cis conformation of the chain. In both cases, the Cu…
O=C(OMe) distance is above 3 Å and can be considered as non-
bonding. Finally, the O-copper cis-dienolate CD2m is best
described as a dicoordinated (k2 coordination) through both C
and O, due to the interaction of the terminal carbon with
copper (CuÀ C=2.03 Å), which is enabled by the cis config-
uration. The CD3m and CD4 m complexes are found to be in
equilibrium through CD2m (see supplementary information for
equilibration TS), and CD1m is too high in energy to be in
significant proportion in the medium, and can easily intercon-
vert to CD4m (see supplementary information for interconver-
sion barriers and transition states structures).
(from 71 to 4%), the amount of the formerly minor isomer 1b
had significantly increased (from 29 to 57%), whereas new
structures 1c, 1d and 1e appeared (Scheme 5).
Computational evaluation of the relative stabilities of these
silyl dienolate isomers reveals that the abundance of isomers
1a–d in presence of the precatalyst experimentally determined
by NMR studies fits closely to their computed relative stabilities.
The two most abundant (1b and 1d) are by far the most stable
whereas 1a, 1c and 1e are more than 1.9 kcalmolÀ 1 higher in
energy.
The observation of silyl dienolates 1a–e underscores an
unexpected and spectacular conformational and stereochemical
scrambling around the two double bonds of the starting
mixture of silyl dienolates 1a,b. The formation of compounds
1c and 1d highlights a E!Z isomerization of the C3=C4
double bond, and compound 1e results from a s-trans to s-cis
$
conformational change in the 1a 1e equilibrium. Whereas the
1a to 1e equilibrium is a simple conformational change, the
increase in the amount of 1b and the appearance of structures
1c and 1d evidence the isomerization of both the C3=C4 (1c
and 1d formation) and the C1=C2 (1b growing from 29 to
57%) double bonds. Considering that these E/Z isomerization’s
are not observed in absence of the catalytic system, it can be
proposed that the equilibration process takes place in the
CuÀ C-enolate complex, whose bonds exhibit a significant
single-bond character (Scheme 6).
The observed conformational/stereochemical scrambling of
the double bonds is in full line with experimental results
obtained starting from silyl dienolate isomers.[6f] Starting either
from silyl dienolate 7 with a C3=C4 double bond of E
Behavior of the solution of Cu-dienolate in catalytic
conditions
The reaction was next conducted in a NMR tube using the
mixture of silyldienolate 1a and 1b and a catalytic amount of
the precatalyst [Cu]F, and was monitored by 2D 1H and 13C NMR
spectroscopy (See SI). Even though the organocopper reagent
generated was in too low concentration to be directly observed
using this procedure, we had interesting NMR results concern-
ing the behavior of the silyldienolates precursor 1a,b. Indeed,
1
1
the silyldienolates 1a,b were characterized by 1D H and 2D H
NOESY NMR experiments (See Supporting Information) as a
well-defined 71:29 mixture of two E/Z diastereoisomers. When
reacted in presence of catalytic amount of the Cu(BINAP)F
precatalyst, a much more complex mixture of silyldienolates
was obtained, and at least 5 different forms could be detected
in the reaction medium (See Supporting Information). Among
them, the initially major form 1a had nearly totally disappeared
Scheme 5. Respective fractions of the silyldienolate isomers observed by
NMR and energies (kcal molÀ 1) relative to the most stable isomer 1b (in red
in parenthesis).
Figure 6. The four most stable optimized Cu-dienolate. Energies of the
minima are given (below structures) in kcal molÀ 1 with respect to the most
stable isomer. Distances (in italic) are given in Å.
Scheme 6. Equilibration of the silyldienolate 1a–d through a copper η1-η3
coordination exchange.
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Conclusion
Through coupling of synthetic, NMR, electrochemical and DFT
studies, we have been able to determine the nature and the
formation pathway of the catalytic system in the Mukaiyama
reaction. The TBAT is shown to play the role of reducing and
fluorinating agent, resulting in a CuF(tolBINAP) precatalyst. The
catalytic active species is proposed to be the Cu-dienolate
species resulting from F/dienolate chain exchange between
Cu(tolBINAP) and SiMe3. This species was characterized compu-
tationally and both CuÀ C and CuÀ O dienolate structures are
described. Nevertheless, the three quasi-isoenergetic structures
described all exhibit a short CuÀ C distance, and either an η3-
terminal coordination or a k2(C,O) bonding. This highlights the
importance of the CuÀ C interaction in shifting the metallotropic
equilibrium toward its formation. In catalytic conditions, this
Cu-dienolate complex is found to carry out slow equilibration
with the remaining silyldienolate and to undergo rapid isomer-
ization along all the dienolate chain. This is the sign of a fast
metallotropic equilibrium within the Cu-dienolate. These find-
ings are the starting point for the determination of reaction
mechanisms for which Cu-dienolates are reaction intermediates
in the presence of electrophiles.
Scheme 7. Observed stereoconvergence in the formation of lactones 2a and
2b starting from the corresponding silyldienolates isomers 7, 8, 11 and 12.
Experimental Section
Computational details: Computations were undertaken using a
simplified chelating disphosphine ligand instead of BINAP, resulting
upon coordination to Cu+ as shown in the complex in Figure 7.
This simple model allowed to sample a large number of structural
arrangements, and to an extend study of the Cu/Si exchange
pathways.
Scheme 8. O-dienolate pathway for identity dienolate chain Cu/Si exchange.
The Energy / Gibbs free energy of the TS is given below its schematic
representation in kcal/mol.
Full geometry optimizations were systematically conducted with no
symmetry restraints using the Gaussian 09 program[21] within the
framework of the Density Functional Theory (DFT) using the PW91
exchange-correlation functional[22] and the 6-31+ +G** basis set
for all atoms as implemented in the Gaussian program. In the case
of the calculation on the complete tolBINAP ligand, the 6-31G** is
used. In the case of the silyldienolate 1a to 1e, the B3PW91
functional[23] associated to Grimme’s Empirical Dispersion (D3
version with Becke-Johnson damping BJ)[24] are used, to include
dispersion effects in the relative stability of all isomers. Solvation
effects are also included using the SMD model,[25] in the standard
implementation in Gaussian, using THF as a solvent. The electronic
plus nuclear energy obtained from SCF and optimization proce-
dures is referred as energy and noted E in the text. Frequencies
were evaluated within the harmonic approximation and used
unscaled to compute Gibbs free energy (G) at 298.15 K using the
standard protocol implemented in Gaussian.
Figure 7. Simplified model for Cu(tol-BINAP).
configuration (obtained from the conjugated ester 9) or from
the corresponding C3=C4 Z double bond isomer 8 (obtained
from the deconjugated ester 10), the same lactone 2a was
obtained with similar yields, diastereo- and enantioselectivities.
Same observations could be drawn from the reactions yielding
the lactone 2b starting from silyl dienolates 11 and 12 obtained
in either 40:60 or 90:10 C1=C2 Z/E mixtures (Scheme 7).
Equilibration between the silyl dienolate thus requires
reversible chain exchange between Cu-enolate and silyldieno-
late, which cannot be confirmed experimentally as no Cu-
enolate could be observed. The chain exchange process was
thus examined computationally in a similar approach than for
the case of the trans O-dienolate pathway described above,
replacing F by dienolate (see Table 2). The obtained TS is
significantly higher than the one obtained for the F/dienolate
exchange. It is nevertheless small enough to justify equilibration
between Cu- and Si-dienolate (Scheme 8).
Experimental details: General Considerations: Experiments were
carried out under dry argon atmosphere. All glassware were dried
°
at 120 C and assembled while hot under a stream of argon. All
moisture-sensitive reactants are handled under a nitrogen atmos-
phere. Low temperature experiments are carried out by cooling
down a three-necked round bottom flask with an ether/acetone
°
(À 80/À 90 C), bath, frozen with liquid nitrogen. The flask was
equipped with an internal thermometer, an argon inlet and a
septum cap. Tetrahydrofuran was distilled from sodium-benzophe-
none ketyl. Copper salts and MeONa were purchased from Aldrich,
kept under argon atmosphere, and dried over P2O5 before use. IR
Chem. Eur. J. 2021, 27, 1–10
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doi.org/10.1002/chem.202100596
Chemistry—A European Journal
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(3E,1Z)-(1-Methoxypenta-1,3-dienyloxy)
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a
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°
Kugelrohr apparatus (45 C, 1 mmHg) to furnish the desired silyl
dienolate as an inseparable mixture. (1 Z/E 71:29, 3 E/Z>98:2).
1
°
For the major product: H NMR (300 MHz, CDCl3, 25 C): 6.10 ppm
(m, 1H), 5.33 (dq, 1H, J=14.9, 6.9 Hz), 4.41 (d, 1H, J=10.3 Hz),
3.56 (s, 3H), 1.72 (dd, 3H, J=1.4, 6.9 Hz), 0.23 (s, 9H). These data
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°
(500 MHz, THF-d8, 25 C): 6.15 (m, 1H), 5.24 (m, 1H), 4.46 (m, 1H),
3.56 (s, 3H), 1.71 (dd, 3H, J=1, 6.5 Hz), 0.29 (s, 9H). 13C NMR
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°
°
(99 MHz, THF-d8, 25 C): 20.2 (s, 1Si).
Electrochemical measurements details: An SP-300 BioLogic appa-
ratus was used for electrochemical experiments. They were carried
out at room temperature, under an argon atmosphere, in a three-
electrode cell containing tetrahydrofuran (THF, 10 mL) as solvent
and tetrabutylammonium tetrafluroborate (TBABF4, 10À 1 mol.LÀ 1) as
supporting salt. The reference electrode was a saturated Hg/Hg2Cl2
reference electrode (noted SCE for Saturated Calomel Electrode)
from Tacussel. It was separated from the cell solution by a bridge
compartment filled with the same solvent / supporting electrolyte
solution as used in the cell. The counter electrode was a platinum
wire. The working electrode was a disk obtained from a cross-
section of a gold wire (d=250 μm) sealed in glass.
Acknowledgements
The authors thank CCR (Univ. Paris VI, Paris, France), CINES
(Montpellier, France), IDRIS (Orsay, France) and CRIHAN (Rouen,
France) for computing facilities, and Clariant and the pro-
gramme franco-algérien de formation supérieure and ANR
Copenol (Projet ANR-09-BLAN-0089) for financial support.
Conflict of Interest
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The authors declare no conflict of interest.
Keywords: ab initio calculations · copper dienolate · reaction
mechanisms · silyl dienolate · structure elucidation
Chem. Eur. J. 2021, 27, 1–10
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© 2021 Wiley-VCH GmbH
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doi.org/10.1002/chem.202100596
Chemistry—A European Journal
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[18] The validation of the ‘small model’ to calculate the transition state of
the TMS/F exchange relies on the comparison of energies of
intermediates CD1 m-CD4 m respectively obtained with the ‘small‘ and
the ‘full‘ model (see Figure 6 and Supporting Information, computation
details section 3). As only slight differences could be observed in these
energies, the small model was thus chosen to compute this TMS/F
exchange barrier. Indeed, only a semi-quantitative assessment of the
activation barrier is necessary to complement our previous mechanistic
studie (ref [17]) and confirms that the TMS/F exchange is not kinetically
hampered.
Manuscript received: February 15, 2021
Accepted manuscript online: March 29, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–10
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© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

FULL PAPER
Dr. B. Lecachey, Dr. L. Palais, Dr. B.
de Courcy, Dr. S. Bouauli, Dr. M. Duran-
detti*, Prof. H. Oulyadi*, Dr. A. Harisson-
Marchand, Dr. J. Maddaluno, Prof. H.
Gérard*, Dr. E. Vrancken*, Prof. J.-M.
Campagne*
An intertwined analytical, experi-
mental and theoretical study disclose
the mechanism of formation of an or-
ganocopper dienolate reagent from
its silylated precursor. The study shed
light on the Cu(II) to Cu(I) reduction
process, the Si to Cu exchange
mechanism and finally the metallo-
tropic equilibrium of the resulting
copper dienolate.
1 – 10
Intertwined Analytical, Experimental
and Theoretical Studies on the
Formation and Structure of a Copper
Dienolate