Stereoselective Access to (E)-1,3-Enynes through Pd/Cu-Catalyzed Alkyne Hydrocarbation of Allenes

Article abstract of DOI:10.1021/acs.orglett.9b00828

Pd^II and Cu^I cooperate in catalyzing the alkynes hydrocarbation of allenes (AHA) giving (E)-1,3-enynes with high yields, atom economy, and high regio-/stereoselectivities. We devised new efficient conditions and expanded the substrat

Full text of DOI:10.1021/acs.orglett.9b00828

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Access to (E)‑1,3-Enynes through Pd/Cu-Catalyzed
Alkyne Hydrocarbation of Allenes
†
†
†
†
†
́
Louis Jeanne-Julien, Guillaume Masson, Remy Kouoi, Anne Regazzetti, Gregory Genta-Jouve,
Vincent Gandon,*,‡,§ and Emmanuel Roulland*,†
†
́
́
C-TAC, UMR 8038, CNRS-Universite de Paris, Faculte de Pharmacie, 4, avenue de l’Observatoire, 75006, Paris, France
‡
́
́
́
́
Institut de Chimie Moleculaire et des Materiaux d’Orsay, CNRS UMR 8182, Universite Paris-Sud, Universite Paris-Saclay,
̂
Batiment 420, 91405 Orsay cedex, France
§
́
Laboratoire de Chimie Moleculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, IP Paris, route de Saclay, 91128, Palaiseau
cedex, France
S
* Supporting Information
ABSTRACT: PdII and CuI cooperate in catalyzing the alkynes
hydrocarbation of allenes (AHA) giving (E)-1,3-enynes with
high yields, atom economy, and high regio-/stereoselectivities.
We devised new efficient conditions and expanded the
substrate scope. Experimental and computational studies
support a nonorthodox PdII/PdIV catalytic cycle involving an
oxidative addition triggered by a stereodeterminant H+
transfer. This reaction is leveraged in a new strategy of
stereoselective synthesis of 1,3-dienes.
This three-step strategy capitalizes on the ability of AHA to
stereoselectively assemble even advanced complex fragments
(Step A), giving (E)-1,3-enynes derivatizable into 1,3-dienes by
regio-/stereoselective hydrosulfuration (Step B),16 and sub-
sequent Pd-nanoparticle-catalyzed methylation, a method we
designed for this aim (Step C).17 Various enyne derivatizations
are imaginable, offering thus a versatile and greener alternative
to traditional strategies relying on olefination reactions (Wittig,
HWE, etc.), and/or transition-metal catalyzed cross-couplings
(Suzuki, Sonogashira, etc.).18 Various AHA protocols8 were
explored on butynol ( )-1a and penta-3,4- dien-1-ol 2a19 that
give enyne 3aa mimicking the synthesis of the tiacumicin B
C11−C17 region. Ultimately, Grigg’s protocol8c proved highly
promising, as it gave good yields, with apparently total regio-/
E-stereoselectivity, under functional-group tolerant conditions.
However, reproducibility issues called for various adjustments:
Pd(OAc)2 was kept as the Pd source (Table 1, entry 1); the
electron-poor P(furan-2-yl)3 was replaced by the electron-rich
(p-MeOC6H4)3P, CuI by CuCl, toluene by THF; and the
reaction was carried out at rt instead of 110 °C. Variations
around the reaction parameters gave instructive insights: A
decrease in catalysts loadings resulted in a slower and less clean
reaction (entry 2). Using CuI altered the yield (entry 3), while
CuOAc increased the reaction rate, but with byproduct
formation (entry 4). In the absence of Cu salt (Trost’s
conditions),8a 3aa was formed in 44% yield because of a
known concurrent reaction involving hydrido-Pd which led to
ransition-metal-catalyzed addition of a terminal alkyne to
Ta nonpolarized π-system acceptor is a direct, atom-
economic way of forging C(sp)−C(sp2) or C(sp)−C(sp3)
bonds from readily accessible reagents. The nonpolarized π-
system acceptors can be alkynes,1,2 1,3-dienes,3 norborna-
dienes,4 norbornenes,5 styrenes,6 cyclopropanes,7 or allenes.8,9
The hydrocarbation of allenes gives 1,3-enynes that, in
addition to the fact they are present in natural products10 or
in materials,11 are also potential precursors of polysubstituted
1,3-dienes.12 The stereoselective synthesis of 1,3-dienes, which
are ubiquitous in natural products, remains a challenging
endeavor, so the development of new strategies is of
paramount importance.13 The complex structure of tiacumicin
B, a naturally occurring antibiotic drug,14 inspired us to
develop an innovative strategy for the construction of the
(E,E)-1,3-dimethyl-butadienylidene motif it contains (Scheme
1):15
Scheme 1. Alkyne Hydrocarbation of Allene (AHA): Its Use
To Access Tetrasubstituted (E,E)-Dienes and Its
Mechanistic Study
Received: March 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00828
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Variations from the Optimized AHA Conditions
Scheme 2. Scope Exploration
entry
variations from the optimized reaction conditions
No variation
Catalytic loadings divided by two
CuI instead of CuCl
CuOAc instead of CuCl
Without Cu salt
yield (%)
1
2
3
4
5
6
7
8
79
66
67
59
44
ab
,
c
d
Without Pd salt
0
de
,
Pd(OCOCF3)2 instead of Pd(OAc)2
PdCl2(PPh3)2 instead of Pd(OAc)2/2(p-MeOC6H4)3P
1.3 equiv of 1a instead of 1 equiv
1.3 equiv of 2a instead of 1 equiv
Toluene instead of THF
PPh3 instead of (p-MeOC6H4)3P
P(furan-2-yl)3 instead of (p-MeOC6H4)3P
Pd2(dba)3 (2.5 mol %) instead of Pd(OAc)2 (5 mol %)
0
b
0
9
100
79
10
11
12
13
14
e
25
a
b
c
64
Yields of isolated products. Various byproducts were formed. No
d
e
starting materials recovered. t = 40 °C.
7
dfg
, ,
38
a
b
c
dienes were investigated: 3aa gave vinylsulfide 5 through OH-
directed hydrosulfuration16 and then, using our Kumada−
Corriu conditions,17 tetrasubstituted 1,3-diene 6 (Scheme 3).
Alternatively, the reaction of 3aa with RedAl, and then with
allyl bromide in the presence of CuCl,20 led to compound 7,
while an H2O quench gave ubiquitous diene 8.
Completed in 3.5 h. Unidentified byproducts. 29% of 4.
d
e
f
Unreacted starting materials recovered. 17 h of reaction. 5 days
g
of reaction. No reaction occurred if 1 phosphine is added per Pd
instead of 2.
allene dimer 4 in 29% yield (i.e., 58% of 2a was transformed)
(entry 5). Without the Pd salt, the reaction failed to proceed
(entry 6). These two experiments illustrate the benefit of
bimetallic Pd/Cu catalysis in the case of AHA. The nature of
the Pd counterions proved fundamental, as no AHA occurred
Scheme 3. Examples of Enyne Derivatization
with CF3CO2 and Cl− (entries 7, 8). Side reactions of allene
−
2a were bypassed by using a sacrificial excess of alkyne 1a,
which delivered 3aa quantitatively (entry 9). Conversely, the
use of an allene excess did not improved the yield (entry 10).
The reaction was very slow in toluene at rt (entry 11), while in
refluxing THF numerous byproducts were formed. Replacing
(p-MeOC6H4)3P by Ph3P decreased yields (entry 12), while
(furan-2-yl)3P led to poor conversions (entry 13). With
Pd2(dba)3 (entry 14), a low level reactivity was observed (5
days, 38%) suggesting that Pd0 does not participate in the
catalytic cycle.
The scope was explored under our optimized reaction
conditions. We studied electron-rich or electron-deficient
substrates, where most of the possible combinations were
explored (21 examples), so together with the previous work,8c
there are now almost 40 examples of AHA described,
illustrating well the efficiency of this reaction (Scheme 2).
3ba and 3ea were obtained with 78% and 67% yields, while
former reaction conditions gave no product. Although
trimethylsilylacetylene gave 3ca in 47% yield, tri-iso-propylsi-
lylacetylene gave enyne 3fa in 81% yield. Electron-poor
ethylpropiolate gave no 3ka. These reaction conditions are
mild and neutral, so 3af was isolated with no alkene/carbonyl
reconjugation. Amide 3ja was obtained in 54% yield, and free
amines proved to be competent reaction partners (3ha: 76%;
3la: 69%). Electron-deficient allenes (2c), or electron-rich
ones (2n), reacted equally well giving 3ac, 3dc, 3gc, and 3an in
good yields. 1-Bromo- and 1-methoxypropa-1,2-diene failed to
give enynes 3aj and 3ak. Enynes 3ad, 3ai, 3ll,15a and 3lm,15b
were obtained in good yields. The two latter were key
intermediates of our two syntheses of the tiacumicin B
aglycon.15 Various derivatizations of 1,3-enynes to give 1,3-
Involving Pd0, hydrido-Pd, and π-allyl-Pd species, the
initially proposed AHA mechanism is certainly orthodox, but
not demonstrated,8c and the following observations tend to
disqualify the involvement of such species. First, Yamamoto
reported that Pd2(dba)3-catalyzed hydrocarbation of 2n by
malonitrile led exclusively to a linear product which proved the
involvement of a π-allyl-Pd here.21 Contradictorily, while a
similar mechanism was postulated, AHA gives only branched
products (even with 2n) and requires a PdII source, Pd2(dba)3
being not an adequate Pd source (Table 1, entry 14). Second,
while TEMPO is known to trap hydrido-Pd complexes,22 its
addition had no impact on the course of the 1a/2a cross-
coupling.23 Third, the 1a/2i cross-coupling gave enyne 3ai
exclusively (Scheme 2), while an ideally positioned OH should
have given tetrahydrofuran 9 by trapping postulated π-allyl-Pd
intermediates (eq 1).24
When a THF solution of Pd(OAc)2 + 2 (p-MeOC6H4)3P
that was stirred for 1.5 h was treated with 1a, 2a, and CuCl, no
B
DOI: 10.1021/acs.orglett.9b00828
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AHA occurs. In contrast, when a THF solution of Pd(OAc)2 +
2 (p-MeOC6H4)3P + CuCl was preincubated for 3 h, and then
treated with 1a and 2a, the reaction goes to completion with
the usual rate and yield.25 We noticed that while CuCl is
insoluble in THF in the presence of (p-MeOC6H4)3P, a THF
solution combining CuCl, Pd(OAc)2, and (p-MeOC6H4)3P is
obtained in minutes, giving a catalytically active deep-orange/
brown solution. This raises the question of the nature of the
reaction catalyst. Amatore and Jutand have shown that mixing
Pd(OAc)2 + 2 PPh3 at rt in THF resulted in a slow reduction
bonding with PdII. The maximum electron density in the Pd···
Cu area is ρmax = 0.023 e·Å, which is typical of weak but non-
negligible metal−metal bonding.31 By locking both acetates,
one can understand how the CuI atom impairs the PdII/Pd0
reduction (Scheme 4, green arrows).26 The overall conclusion
to draw is that this AHA likely involves neither Pd0 nor
hydrido-Pd, nor π-allyl-Pd, and that the catalyst is likely a Pd/
Cu heterobimetallic complex.
With such conclusions, it was deemed necessary to propose
a new reaction mechanism. We carried out DFT computations
to screen the various possibilities. Alkyne 1a and allene 2a were
used as substrates, and Ph3P was used as the model phosphine.
We originally proposed a mechanism that began with the
formation of a (R−CC−)(H)PdIV species, and we also
considered Grigg’s π-allyl-Pd pathway; however, the first
appeared unlikely and the second proved incompatible with
experimental observations.27 Ultimately, the sole viable
mechanism issuing from these calculations is shown in Scheme
5.32 In the absence of an exogenous base, the formation of a
II
0
1
of Pd into Pd by one of the phosphines (t / ∼45 min), a
2
reaction even slower with electron-rich (p-MeOC6H4)3P.26 To
make a blank, we carried out 31P NMR experiments on
Pd(OAc)2 + 2 (p-MeOC6H4)3P (0.015 M/THF).27 As
expected, a signal at 24.2 ppm (p-MeOC6H4)3PO, as well as
other expected signals, appeared progressively attesting to the
reduction of PdII into Pd0.26b Then, 31P NMR experiments
were carried out on the catalytically active Pd(OAc)2 + 2 (p-
MeOC6H4)3P + CuCl mixture.27 Surprisingly, the spectra
recorded were very different from that of the blank: After 3
min all (p-MeOC6H4)3P had already disappeared, and instead
signals at δP 11.9 and 16.7 ppm appeared corresponding to
Pd(OAc)2[(p-MeOC6H4)3P]2 and to an unknown complex α.
After 3 h, only the α complex signal remained. The PdII/Pd0
reduction is slow, so α that forms almost instantaneously is
likely centered on a PdII and is symmetrical since it displays
one single 31P NMR peak. MS experiments were performed on
the same sample.27 Electrospray ionization gave signals at m/z
869.1626 ([L2PdOAc]+) and 845.1157 ([L2PdCl]+).
[L2PdCl]+ shows that Pd2+ and Cu+ can exchange their
counterions, a clue to the Pd/Cu heterobimetallic nature of α.
Then, we shifted to atmospheric pressure photoionization
(APPI), a milder method involving radical processes, and well-
adapted to organometallic complexes.28 Using toluene as a
photoionization dopant, we detected reproducibly a signal at
m/z 933.1808 that corresponds to [L2PdOAc + Cu + H]+
which could form through the pathway drawn in Scheme 4,
confirming the heterobimetallic nature of α.
Scheme 5. Proposed Mechanism Based on DFT
Calculations
Scheme 4. Structure of α Deduced from MS, RMN, and
DFT
Cu acetylide seems unlikely. However, coordination of CuCl to
the alkyne moiety of 1a could assist the formation of a Pd
acetylide. Indeed, from complex α and 1a we could reach intA,
a step endergonic by 13.7 kcal/mol, and we could model a
concerted metalation deprotonation (CMD) with a low free
energy of activation (ΔG‡ = 5.9 kcal/mol). Note that in
298
contrast, CMD of 1a with PdII but without CuI displays a far
higher free energy of activation (ΔG‡ = 15.3 kcal/mol),
298
showing thus the benefit of having here a bimetallic catalysis.33
The transformation of intA is exergonic by 3.2 kcal/mol and
delivers complex intB, exhibiting a noncovalent interaction
between the acidic hydrogen and the acetylide carbon. The
reaction of Pd acetylide intB with allene 2a then gives simple
adduct intC, lying at 5.7 kcal/mol on the potential energy
surface. A H+ transfer on the allene34 from the protonated
acetate ligand then follows to give intD. This complex was
actually optimized as a vinylic carbocation35 (as revealed by
inspection of its LUMO), which lies 4.8 kcal/mol above
reference compounds intA and 2a. The protonated allene is
held by two H-bonds with the acetate ligands. The formation
Ultimately we used density functional theory (DFT) to
model complex α.29 Calculations converged toward a complex
displaying a 2.90-Å-long PdII−CuI contact, a length typical of
group 10/group 11 heterobimetallic complexes involving a
PdII.30 The PdII atom is square planar, while the CuI atom
shows a trigonal planar geometry with an additional apical
C
DOI: 10.1021/acs.orglett.9b00828
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the Pd−C bond from intD to give the pentavalent vinyl PdIV
species18,36 intE requires only 1.0 kcal/mol of free energy of
activation and is appreciably exergonic by 17.7 kcal mol−1. It is
noteworthy that a similar oxidative addition initiated by
protonation of a nonpolarized π-system has been recently
reported in a case of rhodium catalysis.37 The reductive
elimination transition state (TS) is also easily accessible (6.3
kcal/mol of free energy of activation from intE), and this C−C
bond forming step releases 45.3 kcal/mol of free energy. The
final PdII complex intF displays the experimentally observed
stereochemistry. Calculations were reproduced to obtain
unobserved (Z)-3aa. In that case, the R2 chain in the TS has
a steric clash with an acetate ligand, and one stabilizing H-
bond is missing (Frame, Scheme 5). The free energy of
activation is 3.3 kcal/mol higher than in E series, which is
perfectly enough to ensure virtually complete diastereoselec-
tivity at 20 °C as observed experimentally. This mechanistic
model accurately describes our experimental observations;
however, it is also predictive, which validates it. Thus,
calculations show that the pathway from intC to intD is rate
determining and that intD is stabilized by H-bonds involving
Pd-counterions. Our model predicted that the reaction rate
depends on the pKa of the Pd counterions, since H-bond
strength and the pKa of counterions are linked together.
Stronger H-bonds are provided by anions from weak acids;
therefore, higher reaction rates are expected with them.24 We
calculated that the free energy of activation to go from intC to
intD is 15.7 kcal/mol with acetates, 16.2 kcal/mol with
benzoates, 17.1 kcal/mol with 3-fluorobenzoates, and with
trifluoroacetate no value could be found. To our delight, DFT
predictions were experimentally confirmed: the reaction rate
decreases well with the pKa (PivO− (5.03) ≈ AcO− (4.76) >
PhCOO− (4.20) > 3-fluoro-benzoate (3.86), and trifluoroace-
tate (0.23) allowed no reaction).38
This re-exploration of the Pd/Cu-catalyzed AHA led to
devising new reliable conditions, to enlarge the substrate scope,
to evaluate functional tolerance, and to devise an innovative
strategy of synthesis of 1,3-dienes that proves remarkably
useful to total synthesis. A series of observations were not in
agreement with the originally proposed mechanism. So,
supported by DFT calculations, NMR, MS, and chemical
experiments, we propose a mechanism which proved non-
orthodox but coherent. It involves a PdII/PdIV catalytic cycle,
TSs tightly organized by H-bonds with the Pd counterions, and
an oxidative addition initiated by a stereodeterminant H+
transfer. We also suggest that the catalyst is a heterobimetallic
complex. We hope that this mechanism will help in the design
of new reactions and that our strategy of synthesis of 1,3-
dienes will find more applications in synthesis.
*E-mail: vincent.gandon@u-psud.fr.
ORCID
́
Gregory Genta-Jouve: 0000-0002-9239-4371
Vincent Gandon: 0000-0003-1108-9410
Emmanuel Roulland: 0000-0002-8012-7946
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the ANR (ANR-14-CE16-0019-02), the
■
́
́
CNRS, the Universite de Paris, the Universite Paris-Saclay, and
the Institut Universitaire de France (IUF) for financial support.
We thank Pr. Olivier Laprevote (C-TAC, UMR 8038) for the
fruitful discussions about mass spectroscopy.
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Experimental details and characterization data for all
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Corresponding Authors
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*E-mail: emmanuel.roulland@parisdescartes.fr.
D
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F
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