Kinetically Controlled Stereoselective Access to Branched 1,3-Dienes by Ru-Catalyzed Remote Conjugative Isomerization

Article abstract of DOI:10.1021/acscatal.1c02144

A Ru-catalyzed conjugative isomerization of remote alkenes that affords branched 1,3-dienes is described. These kinetic products are obtained in high yields, good levels of regiocontrol, and high stereoselectivity. A broad range of functional groups and heterocycles are compatible with the mild reaction conditions, and isomerization is sustained over long distances. Control experiments support a metal-hydride mechanism consisting of iterative migratory insertions/β-H eliminations, which is initiated preferentially at the terminal olefinic site. Two one-pot multimetallic selective catalytic sequences using [Ru/Cu] and [Ru/Rh] combinations have been developed to illustrate the synthetic potential of the process.

Full text of DOI:10.1021/acscatal.1c02144

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Research Article
Kinetically Controlled Stereoselective Access to Branched 1,3-Dienes
by Ru-Catalyzed Remote Conjugative Isomerization
Simone Scaringi and Clément Mazet*
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ABSTRACT: A Ru-catalyzed conjugative isomerization of remote alkenes that affords branched 1,3-dienes is described. These
kinetic products are obtained in high yields, good levels of regiocontrol, and high stereoselectivity. A broad range of functional
groups and heterocycles are compatible with the mild reaction conditions, and isomerization is sustained over long distances.
Control experiments support a metal-hydride mechanism consisting of iterative migratory insertions/β-H eliminations, which is
initiated preferentially at the terminal olefinic site. Two one-pot multimetallic selective catalytic sequences using [Ru/Cu] and [Ru/
Rh] combinations have been developed to illustrate the synthetic potential of the process.
KEYWORDS: ruthenium catalysis, isomerization, 1,3-dienes, remote functionalization, stereocontrol, kinetic control
n addition to being a highly prevalent structural element in
numerous natural products and biologically active molecules,
accessible substitution patterns. In 2000, an isolated example of
Ru-catalyzed deconjugative isomerization of an α,β-unsaturated
ester producing a linear diene with a reduced level of
stereocontrol was disclosed by Mori and co-workers.10 Inspired
by precedents from Negishi, the Marek group reported a one-
pot isomerization/elimination sequence, which delivers geo-
metrically pure linear or branched dienes starting from alkenyl
methyl vinyl ethers. In this system, long-range isomerization of
the remote alkene is mediated by a stoichiometric amount of a
zirconocene derivative and is followed by simple hydrolysis.11
Diver developed a [Ru−H]-catalyzed stereoconvergent posi-
tional isomerization of branched dienes resulting from an ene−
yne metathesis into the thermodynamically more stable linear
isomers.12 The reaction can be conducted in a single vessel
starting from simple alkynes and alkenes and by triggering
decomposition of the alkylidene metathesis catalyst into an
isomerization catalyst using vinyloxytrimethylsilane.13
I
conjugated dienes serve as pivotal building blocks in the
synthesis of a broad range of compounds, ranging from fine
chemicals to functional polymers (Figure 1A).1−3 Because the
inherent reactivity of dienes is influenced by the nature, the
number, and the relative position of their substituents, they also
constitute a particularly modular and versatile platform for the
discovery and development of catalytic synthetic methods that
streamline access to more complex polyfunctional small
molecules. More specifically, beyond any reactivity consider-
ation, transition-metal-catalyzed functionalization of dienes is
typically faced with the difficulty of exerting excellent chemo-,
regio-, diastereo-, and enantiocontrol.4
To date, the stereoselective synthesis of substituted 1,3-dienes
still represents a considerable challenge.5 Conjugated dienes are
most commonly prepared by conventional non-atom econom-
ical olefinations of carbonyl precursors or by stereoretentive
cross-coupling reactions using stereochemically well-defined
starting materials.6 Approaches based on C−H activation,
photoredox catalysis, and metathesis have also been described.7
Notably, the stereoselective preparation of substituted dienes
has been achieved by rearrangements, transpositions, or
isomerizations of allenes and alkynes, albeit with a narrow
substrate scope.8 Examples of conjugated dienes obtained by
alkene isomerization are scarce (Figure 1B).9 This is surprising
because such redox economic strategies could offer increased
flexibility and generality, in particular, for the preparation of less
We have recently initiated a program aimed at developing
remote functionalization strategies based on alkene isomer-
ization.14−16 As part of these investigations, we wondered
Received: May 12, 2021
Revised: June 3, 2021
Published: June 16, 2021
https://doi.org/10.1021/acscatal.1c02144
© 2021 American Chemical Society
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Figure 1. (A) Industrially relevant and bioactive naturally occurring conjugated dienes highlighting the diversity of substitution patterns. (B)
Precedents in metal-catalyzed and metal-mediated isomerization strategies to access conjugated dienes. (C) Challenges associated with the
development of a [M-H]-catalyzed conjugative isomerization to access branched dienes.
whether branched 1,3-dienes could be stereoselectively accessed
by bringing in conjugation two distant carbon−carbon double
bonds using well-defined transition metal hydride catalysts
(Figure 1C). To achieve this goal, we anticipated that it was
necessary to identify a system able to (i) distinguish between
two minimally differentiated olefins, (ii) sustain migration over
several methylene units, (iii) operate under mild conditions to
favor formation of the branched dienes rather than the
thermodynamically more stable linear isomers, (iv) induce
stereocontrol, and (v) display broad functional group tolerance.
Moreover, in addition to potential directionality issues upon
migration of the CC bond(s), it was unclear whether a remote
alkene would constitute a sufficiently strong driving force to the
overall process. Indeed, examples of long-range isomerization
where the end group does not possess a heteroatom are less
common.10,15g,17 Finally, we also hypothesized that, if generated
preferentially, branched dienes may act as a catalyst inhibitor by
forming a stable chelate with a transition-metal complex or
engage in parasitic cycloaddition reactions.
To address these challenges, we began our investigations by
evaluating a series of established isomerization precatalysts
(C1−C8; 5 mol %) using vinylarene 1a as a model substrate
(Table 1). The reactions were monitored over 24 h by 1H NMR
in CD2Cl2, a noncoordinating solvent to avoid competing
binding with the substrate and with a temperature never
exceeding 60 °C. Group IX catalytic systems C1−C2 and our
homemade Pd complex (C3) led essentially to the 1-carbon
isomerization product 2a with poor stereocontrol, while only
traces of 3a and 4a were detected (entries 1−4).15 With the
protocol developed by Nelson and modified by Marek
([Ir(cod)Cl]2/PCy3/NaBArF; C4) or with Grotjahn’s catalyst
C5, the targeted branched diene 3a was generated preferentially
with a high level of stereoselectivity (Entries 5−6).18,19
Nonetheless, the substantial amount of 2a and 4a and the
similar polarity of all three isomeric products prevented efficient
purification. The marked differences between the structurally
closely related hydrido-ruthenium complexes C6−C8 is
particularly noteworthy because each of them displayed distinct
regioselectivity (entries 7−9). While, chlorohydridotris-
(triphenylphosphine) ruthenium C6 produced exclusively 4a,
in turn, C7 generated 2a as the major regioisomer. By contrast,
C8 afforded branched diene 3a preferentially with excellent
stereoselectivity (E/Z > 20:1).17a The effect of the added ligand
was explored next and revealed that the addition of 5 mol % PPh3
had a beneficial impact on product distribution without
deterioration of the stereoselectivity (entries 10−15). Addi-
tional control experiments confirmed that at higher temper-
atures, the thermodynamically more stable linear diene 4a could
be formed exclusively, albeit with a poor level of stereocontrol
(entries 16−18).20,21
Gratifyingly, with the optimized conditions disclosed in entry
14 (Table 1), purification was greatly facilitated and branched
diene 3a was isolated in pure form in a 70% yield (E/Z > 20:1).
Similar performances were obtained when this experiment was
conducted on a gram scale. Therefore, the scope of selective
isomerization was explored using this protocol (Figure 2).
Variation of the electronic properties of the vinylarene end
group was well tolerated. Electron-rich, electron-neutral, and
electron-deficient aromatic rings led to consistently appreciable
catalytic performances, be it in terms of reactivity, regio-, or
stereoselectivity (3a−k). Substituents could be indifferently
installed in para, meta, and ortho positions, the latter providing
the highest regioisomeric ratio and consequently the highest
yield (3j,k). In addition to alkyl ether, aryl ether, silyl ether,
bromide, and chloride, which were found to be compatible with
the reaction conditions, heteroaromatics such as a pyridine (3l),
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prepared by this approach.22 Even though the stereoselectivity
was lower in this case (E/Z = 5:1), this example illustrates the
exquisite chemoselectivity of the [Ru−H] catalyst because four
distinct alkenes are present in the substrate/product. Remark-
ably, a benzylic stereocenter in the α-position to the 1,1-
disusbtituted alkene was not enantiomerized as demonstrated
with the enantiospecific isomerization of 1t into 3t. Finally, with
proper adjustment of the reaction time, long-range conjugative
isomerization was achieved without noticeable reduction of the
catalytic performances with up to five methylene units between
each olefinic moiety (3u−w).
a
Table 1. Catalyst Survey
The limits of our protocol were further explored by subjecting
a substrate terminated by a stereodefined vinyl ether (E)-5a to
the optimized reaction conditions (Figure 3A). Gratifyingly, the
corresponding conjugated dienyl ether (E,E)-6a was isolated in
65% with excellent stereocontrol (EE > 20:1). We also found
that an α,β-unsaturated ester (7a) could be deconjugated to
produce preferentially a conjugated branched 1,3-diene (8a, E/
Z > 20:1, 53% yield) (Figure 3B).
To gain insights into the origin of the regio- and chemo-
selectivity, preliminary mechanistic experiments were con-
ducted. The Ru-catalyzed remote isomerization of a geminally
dideuterated substrate at C1 (1b-d2) was particularly instructive
(Figure 4A). While a substantial decrease of the deuterium
content at C1 was noted, D incorporation was measured at C3,
C4, C5, and C6. These observations are consistent with a metal-
hydride mechanism in which: (i) migratory insertion across
C1C2 is reversible and produces catalytically competent
[Ru−D] species, (ii) the terminal olefin is isomerized via
iterative migratory insertion/β-H elimination sequences, and
(iii) incorporation at C3 occurs after formation of the branched
1,3-diene 3b. This last conclusion is further supported by the
results of the experiment disclosed in Figure 4B. Indeed, when a
pure sample of 3a was resubjected to the optimized reaction
1
conditions and monitored by H NMR spectroscopy, gradual
formation of linear diene 4a was accompanied by the appearance
of deconjugated diene 2a. This suggests that 2a is a likely
precursor to 4a, the latter being produced by [Ru−H] insertion
across C1C2 and subsequent β-H3 elimination. Finally,
exposing 3a to the catalytic combination C8/PPh3 in refluxing
toluene led to the exclusive formation of a complex stereo-
isomeric mixture of the thermodynamically more stable
regioisomer 4a (Figure 4C). We found that the stereochemical
purity of a 2:1 E/Z mixture of 3f could be improved to >20:1
within 8 h by subjecting it to our optimized reaction conditions
(Figure 4D). This prompted us to apply this protocol to diene 3x
(E/Z 6:1), prepared independently by a Ru-catalyzed ene−yne
metathesis. Perfect stereocorrection was achieved within 10 h
without traces of other regioisomeric products. This result
complements those obtained by Diver.12 We anticipate this
approach may be systematized because intermolecular ene−yne
metathesis generally produces stereoisomeric mixtures (typical
E/Z ratio ranges from ∼1:1 to ∼5:1).23 Importantly, we noted
that while developing Ru-catalyzed addition of aldehydes to
dienes, Ryu and co-workers observed the quantitative formation
of a π-allyl ruthenium complex within ∼15 min when C8 was
reacted with 1.0 equiv of isoprene in CDCl3 at 90 °C.20,24,25
When a similar experiment was conducted using equimolar
amounts of C8, PPh3 and 3a at 60 °C, we could not detect
formation of analogous π-allyl intermediates as no apparent
reaction occurred based on 1H and 31P NMR spectroscopy (see
the SI for details). Overall, the results presented in Figure 4 put
into further perspective the perfect enantiospecific nature of the
a
Reactions conducted in a J-Young NMR tube: 1a (0.05 mmol).
b
c
Determined by 1H NMR using an internal standard. Major
regioisomer was obtained as a mixture of stereoisomers (see the
Supporting Information (SI)). H2 activation. 5 mol % NaBArF. 30
mol %. 12.5 mol % NaBArF. 5 mol %. 10 mol %. 30 h. In toluene-
d8.
d
e
f
g
h
i
j
k
a benzothiophene (3m), and a pyrazole (3n) were also
tolerated. A more congested 2,3,4-substituted conjugated
diene could be prepared using this method (3o). Quite notably,
alkyl containing substrates were also isomerized successfully to
the kinetic product, thus highlighting the possibility to access
diversely substituted 1,3-dienes with this strategy. A sterically
demanding 1-adamantyl substituent (3p), a cyclohexyl (3q),
and a phenethyl moiety (3r) gave satisfactory results. Of note,
the similar physicochemical properties of the regioisomeric
cyclohexyl products prevented efficient purification, further
highlighting the necessity to achieve excellent selectivity.
Starting from a perillic acid derivative, [3]-dendralene 3s,
which possess a potentially labile allylic stereocenter, was also
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Figure 2. Scope of the Ru-catalyzed conjugative isomerization of dienes (0.3 mmol scale, unless otherwise noted). The yield was reported for the pure
major regioisomer, isolated by column chromatography (except 3p and 3s). Stereoselectivity (E/Z) was determined by 1H NMR using an internal
standard. The regioisomeric ratio (rr) is expressed as the ratio between 3 and all other isomers (2 + 4) as determined by 1H NMR using an internal
standard. aIn toluene. b90 °C. c48 h. d80 °C. e72 h. f Enantiomeric excess was determined by high-performance liquid chromatography (HPLC) using a
chiral stationary phase. g120 h.
Figure 3. Ru-catalyzed conjugative isomerization of electronically biased substrates. The yield was reported for the major regioisomer after
1
purification. Stereoselectivity (E/Z) was determined by H NMR with an internal standard. The regioisomeric ratio (rr) is expressed as the ratio
between 6a or 8a and all other isomers as determined by 1H NMR using an internal standard.
isomerization of 1t into 3t (Figure 2). Retrospectively, the high
level of regioselectivity obtained for the sterically more
demanding substrates (1j,k, 1m, 1p, 1w) may also be ascribed
to the limited ability of the Ru−H catalyst to insert across the
1,1-disubstituted alkene moiety.
The synthetic utility of our approach was established by
conducting a series of one-pot processes (Figure 5). We showed
that the Ru-catalyzed conjugative isomerization can be
combined with [4 + 2] cycloaddition reactions using either an
electron-deficient dienophile such as dimethyl acetylenedicar-
boxylate or nitrosobenzene to afford cycloadducts 9a and 10y in
62 and 64% yields, respectively (Figure 5A,B). Noticeably, 10y
was isolated as a single regioisomer.26 Based on our mechanistic
investigations, the cycloadditions were performed at 60 °C to
avoid extensive formation of nonconjugated dienes 2 and linear
dienes 4.
In recent years, the development of selective catalytic
methods using cyclic or linear dienes has flourished.4c−f To
date, protocols based on dienes with a 2,4-disubstitution pattern
are much less common. Pleasingly, we found that the Ru-
catalyzed conjugative isomerization could be effected in THF
sequentially with a Cu-catalyzed protoboration of the in situ
generated diene, followed by a classical oxidative work-up
procedure. Quite remarkably, among the dozen of possible
isomeric structures that can be generated theoretically,
homoallylic alcohol (E)-11k, resulting from a formal 1,2-
borylation, was obtained preferentially in a 74% yield (Figure
5C).4f,27 The Dong group recently reported a highly
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Figure 4. Preliminary mechanistic investigations. (A) Labeling
experiments. (B) Postcatalytic isomerization of 3a. (C) Isomerization
of 3a under thermodynamic reaction conditions. (D) Stereocorrective
isomerizations.
regioselective Rh-catalyzed Markovnikov 1,2-hydrothiolation of
2-substituted 1,3-dienes.28 To explore the compatibility of this
system with our conjugative isomerization protocol, 1c was
engaged in a multimetallic [Ru/Rh] catalytic sequence (Figure
5D). Unexpectedly, allyl aryl sulfide (E)-12c was produced in
majority with a high level of stereocontrol. Upon inspection of
the crude reaction mixture, the expected 1,2-addition product
was detected in a minor amount along with traces of other
regioisomers. Beyond considerations of catalyst affinity in
multimetallic reactions,15g this result further underscores the
impact of the diene substitution pattern on the outcome of
established selective catalytic methods.
In summary, using a commercially available ruthenium
hydride complex, we have developed an operationally simple
protocol that affords branched 1,3-dienes by conjugative
isomerization of two remote alkenes. These kinetic products
are obtained preferentially over the thermodynamically more
stable linear isomers by conducting the reaction at temperatures
not exceeding 60 °C and in the presence of a catalytic amount of
triphenylphosphine. A variety of functional groups and hetero-
cycles are well tolerated and isomerization can be sustained over
several methylene units. Preliminary investigations point to a
metal-hydride mechanism consisting of repeated migratory
insertions/β-H eliminations, while sterically demanding sub-
strates limit the contribution of competing pathways by
increasing chemoselective insertion across the terminal olefin.
Two one-pot sequential multimetallic selective catalytic
sequences using [Ru/Cu] and [Ru/Rh] couples have been
Figure 5. One-pot catalytic processes. (A) and (B) Ru-catalyzed
conjugative isomerization/[4 + 2] cycloadditions. (C) Ru-catalyzed
conjugative isomerization/Cu-catalyzed protoboration followed by
alkali oxidation. (D) Ru-catalyzed conjugative isomerization/Rh-
catalyzed hydrothiolation.
developed. They are intended to serve as blueprints for the
discovery of related enantioselective processes. Work is
currently underway in our laboratories to tackle these
challenges.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02144.
■
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Experimental procedures and characterization of all new
compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Clément Mazet − Department of Organic Chemistry, University
of Geneva, 1211 Geneva, Switzerland; orcid.org/0000-
0002-2385-280X; Email: clement.mazet@unige.ch
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(b) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Recent advances in efficient and selective synthesis of di-, tri-, and
tetrasubstituted alkenes via Pd-catalyzed alkenylation-carbonyl olefi-
nation synergy. Acc. Chem. Res. 2008, 41, 1474−1485. (c) De Paolis,
M.; Chataigner, I.; Maddaluno, J. Recent Advances in Stereoselective
Synthesis of 1,3−Dienes. Top. Curr. Chem. 2012, 327, 87−146.
(d) Hubert, P.; Seibel, E.; Beemelmanns, C.; Campagne, J−M.; de
Figueiredoa, R. M. Stereoselective Construction of (E,Z)-1,3-Dienes
and Its Application in Natural Product Synthesis. Adv. Synth. Catal.
2020, 362, 5532−5575. (e) Soengas, G. R.; Rodríguez−Solla, H.
Modern Synthetic Methods for the Stereoselective Construction of
1,3−Dienes. Molecules 2021, 26, No. 249.
Author
Simone Scaringi − Department of Organic Chemistry,
University of Geneva, 1211 Geneva, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02144
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Swiss National Science
Foundation (200021_188490) and the University of Geneva.
The authors thank Anthony Adam and Florian Dubler
(University of Geneva) for technical assistance. Stéphane Rosset
(University of Geneva) is acknowledged for measuring HRMS.
Daniele Fiorito (University of Geneva) is acknowledged for
fruitful scientific discussion.
(6) For selected examples see: (a) Ruijter, E. J.; Shultingkemper, H.;
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Hetero−Diels−Alder Reactions of 2−Alkenals with Stereochemical
Induction from Chiral Dienes. J. Org. Chem. 2005, 70, 2820−2823.
(b) Huang, Z.; Negishi, E.-I. Highly Stereo− and Regioselective
Synthesis of (Z)-Trisubstituted Alkenes via 1−Bromo−1−alkyne
Hydroboration−Migratory Insertion−Zn−Promoted Iodinolysis and
Pd−Catalyzed Organozinc Cross−Coupling. J. Am. Chem. Soc. 2007,
129, 14788−14792. (c) Markiewicz, J. T.; Schauer, D. J.; Lofstedt, J.;
Corden, S. J.; Wiest, O.; Helquist, P. Synthesis of 4−Methyldienoates
Using a Vinylogous Horner-Wadsworth−Emmons Reagent. Applica-
tion to the Synthesis of Trichostatic Acid. J. Org. Chem. 2010, 75,
2061−2064. (d) Zheng, C.; Wang, D.; Stahl, S. S. Catalyst−Controlled
Regioselectivity in the Synthesis of Branched Conjugated Dienes via
Aerobic Oxidative Heck Reactions. J. Am. Chem. Soc. 2012, 134,
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