Hydrogenative metathesis of enynes via piano-stool ruthenium carbene complexes formed by alkyne gem-hydrogenation

Article abstract of DOI:10.1021/jacs.0c07808

The only recently discovered gem-hydrogenation of internal alkynes is a fundamentally new transformation, in which both H atoms of dihydrogen are transferred to the same C atom of a triple bond while the other position transforms into a discrete metal carbene complex. [Cp?RuCl]4 is presently the catalyst of choice: the resulting piano-stool ruthenium carbenes can engage a tethered alkene into either cyclopropanation or metathesis, and a prototypical example of such a reactive intermediate with an olefin ligated to the ruthenium center has been isolated and characterized by X-ray diffraction. It is the substitution pattern of the olefin that determines whether metathesis or cyclopropanation takes place: a systematic survey using alkenes of largely different character in combination with a computational study of the mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the stability of the secondary carbene complex formed, if metathesis were to take place. The first application of "hydrogenative metathesis"to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides opportunities for C-H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis, which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru-Cl] bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental confirmation provided herein has implications beyond the present case.

Full text of DOI:10.1021/jacs.0c07808

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Article
Hydrogenative Metathesis of Enynes via Piano-Stool Ruthenium
Carbene Complexes Formed by Alkyne gem-Hydrogenation
̈
Sebastian Peil, Giovanni Bistoni, Richard Goddard, and Alois Furstner*
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ABSTRACT: The only recently discovered gem-hydrogenation of
internal alkynes is a fundamentally new transformation, in which both
H atoms of dihydrogen are transferred to the same C atom of a triple
bond while the other position transforms into a discrete metal carbene
complex. [Cp*RuCl]4 is presently the catalyst of choice: the resulting
piano-stool ruthenium carbenes can engage a tethered alkene into either
cyclopropanation or metathesis, and a prototypical example of such a
reactive intermediate with an olefin ligated to the ruthenium center has
been isolated and characterized by X-ray diffraction. It is the substitution
pattern of the olefin that determines whether metathesis or cyclo-
propanation takes place: a systematic survey using alkenes of largely
different character in combination with a computational study of the
mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with
predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the
stability of the secondary carbene complex formed, if metathesis were to take place. The first application of “hydrogenative
metathesis” to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of
these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides
opportunities for C−H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis,
which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru−Cl]
bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously
been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental
confirmation provided herein has implications beyond the present case.
the same probability;2,3 polarization of the triple bond and/or
incorporation of a propargylic substituent able to ligate the Ru
INTRODUCTION
The catalytic gem-hydrogenation of internal alkynes is a
■
center tips the scales such that gem-hydrogenation becomes the
dominant or even exclusive course.2,3 Moreover, a distinct
correlation between the electronic properties of the ancillary
CpX ligand and the ease of gem-hydrogenation was
established.7
Details apart, the generation of discrete metal carbene
complexes via gem-hydrogenation of an alkyne provides an
attractive outlook:1 if one is able to either block or outcompete
the steps downstream of C that lead to the E-alkene F, this
process might be diverted and genuine carbene chemistry
might be harnessed (Scheme 1). To this end, we pursued
different lines of research and were able to achieve a proof of
fundamentally new reactivity mode: it allows both H atoms of
dihydrogen to be transferred to the same C atom of a triple
bond, whereas the second C atom is concomitantly trans-
formed into a discrete metal carbene.1 This unprecedented
outcome was originally discovered during mechanistic studies
into the equally perplexing trans-hydrogenation of alkynes with
the aid of [Cp*Ru]-based catalysts (Scheme 1).2−4
The reaction commences with the upload of the substrate
and H2 onto the ruthenium catalyst as shown in A, followed by
a first hydrogen transfer to the π system activated by the
carbophilic metal fragment.5 If the second H atom is delivered
to the Cα position, the resulting ruthenacyclopropene B6
evolves in a concerted manner into complex E, from which the
E-olefin F is released. Competing transfer to Cβ, however,
constitutes the actual “gem-hydrogenation” event: the resulting
piano-stool ruthenium carbene C flanked by the newly formed
methylene group can also transform into alkene F, provided
that a second molecule of H2 binds to the metal center to
lower the barriers. For an unbiased substrate such as 2-butyne,
the two interwoven pathways were computed to have basically
Received: July 20, 2020
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Scheme 1. Link between trans-Hydrogenation and gem-
Hydrogenation
Scheme 2. Representative Example Showing the Effect of
the Degree of Substitution on the Reaction Outcome
a
membered rings; all attempts at making larger cycles have so
far met with failure likely because of the kinetic handicap in
closing medium-sized or macrocyclic rings, which allows the
competing trans-hydrogenation of the enyne via C and D
(with/without over-reduction) to prevail. Moreover, the use of
substrates containing (electron-rich) arenes, 1,3-dienes, or
related motifs that bind more tightly to the [Cp*Ru] fragment
than to the triple bond to be gem-hydrogenated was usually
met with failure; likewise, competing cycloisomerization was
observed for certain enyne substrates (for representative
examples, see the Supporting Information).22 On the other
hand, it is noteworthy that all products formed by “hydro-
genative metathesis” are trisubstituted olefins, which are not
necessarily easy to make even with the aid of classical (first-
generation) Grubbs-type catalysts; this is particularly true for
trisubstituted butenolides or cyclic ketones such as 5−8, which
posed significant challenges in the past but are well within the
reach of this new methodology (Scheme 3).12,23,24
a
The steps of the trans-hydrogenation pathway downstream of C that
need to be blocked or outperformed in order to harness genuine
carbene chemistry are shown as dotted arrows.
concept in more than one format: novel hydrogenative skeletal
rearrangements,3 hydrogenative heterocycle syntheses,3,8 coun-
terintuitive “hydrogenative cyclopropanation” reactions,3,9,10
and even a “hydrogenative metathesis” manifold have been
discovered.9,11 The present report is focused on this last
transformation, which converts an enyne into a cycloalkene
rather than into a 1,3-diene as conventional enyne metathesis
would.12,13 Therefore, it embodies a new paradigm in
metathesis. A combined experimental and computational
approach provided insights into the factors controlling the
reaction outcome and led to a refined mechanistic picture of
this unorthodox transformation.
Scheme 3. Trisubstituted Cyclic Ketones and Butenolides
Formed by “Hydrogenative Metathesis”
RESULTS AND DISCUSSION
■
Reaction Development. Cognizant of the need to steer
gem-hydrogenation with the aid of a propargylic substituent,1−3
we initially chose enynes of type 1 as model substrates. As
previously described, the outcome of the reaction is largely
determined by the substitution of the olefinic site (Scheme
2):9 while hydrogenation of 1b comprising a terminal alkene
with [Cp*RuCl]4 as a precatalyst in 1,2-dichloroethane at an
elevated temperature furnished cyclopropane 3b, its sibling 1a
containing two methyl substituents on the alkene gave the
metathesis product 2a under otherwise identical condi-
tions.14,15 This strikingly divergent behavior proved to be
general;9 it came as a surprise in view of earlier literature
reports which had found that putative carbene complexes of
the type [Cp*Ru(Cl)(CR2)] generated in situ from diazo
precursors are highly competent in cyclopropanation but
essentially failed to effect olefin metathesis.16−21
Total Synthesis of Sinularones E and F by Hydro-
genative Metathesis. To assess this valuable aspect more
closely, two unusual cyclopentenone derivatives isolated from a
Sinularia octocoral collected off Hainan Island were chosen for
a first application of the novel hydrogenative metathesis in the
realm of natural product chemistry.25,26 The assignment of the
relative stereochemistry of sinularones E and F, which differ
only in the configuration of C7, is solely based on computed
13C NMR shifts and computed specific rotations and hence
mandates experimental confirmation. From a synthetic view-
point, these targets provide a rigorous testing ground for the
new methodology because the gem-dimethyl group flanking the
trisubstituted alkene to be metathesized entails notable steric
These hydrogenative transformations work well as long as
the propargylic substituent is a tertiary ether, silyl ether, or
acetal, as illustrated by a range of diverse products (see ref 9
and the Supporting Information). For the time being, the
reactions are limited to the formation of five- and six-
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a
hindrance (Scheme 4). Since hydrogenative metathesis
requires a noncoordinating solvent, the presence of a cis-
Scheme 5
Scheme 4. Structures and Retrosynthetic Analysis of
Sinularones E and F
configured tetrahydrofuran moiety in the target compound was
another point of concern, because it might entail the formation
of an unfavorable six-membered chelate complex with the
transient Lewis acidic carbene center.27
The required diastereomeric enyne substrates were readily
attained starting from the cheap furan 11 (Scheme 5). On
hydrogenation over Rh/Al2O3, saturation of the aromatic ring
precedes reduction of the ketone and hence allows the cis-
configured tetrahydrofuran 12 to be obtained on a gram scale,
provided the reaction is properly monitored (see the
Supporting Information).28,29 The subsequent addition of
acetylide needed careful optimization because 12 is readily
enolized on treatment with commercial HCCMgBr at low
temperature, leading to a complex mixture comprising the self-
aldolization product 13 (mixture of isomers) as major
constituent. The problem was remedied by the addition of
LaCl3·2LiCl to temper the basicity of the organometallic
reagent.30,31 Under these conditions, the propargyl alcohols 14
were obtained in 74% combined yield (66% on a 7.4 mmol
scale). As one might expect from a highly oxophilic Lewis acid,
the major diastereomer 14a formed in the presence of La(3+)
corresponds to the Cram-chelate adduct.32 The epimers 14a
and 14a′ are readily separable, and both yielded single crystals
suitable for X-ray diffraction (see the Supporting Informa-
tion);33 as the corresponding carbinol center in sinularones E
and F is the one that needs experimental proof, a sound basis
for the completion of the total synthesis was reached.
a
Reagents and conditions: (a) H2 (1 atm), Rh/Al2O3 (1 mol %),
Et2O, 59% (16 mmol scale); (b) HCCMgBr, THF, −78 °C → RT,
44% (dr = 1.4:1); (c) LaCl3·2LiCl, THF, then HCCMgBr, 0 °C,
66−74% (dr = 4:1) (gram scale); (d) SEMCl, iPrNEt2, CH2Cl2, 94%;
(e) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C → RT, 97%; (f) TMSOTf,
2,6-lutidine, CH2Cl2, 0 °C, 92%; (g) nBuLi, THF, 0 °C, then 18, −78
°C (−50 °C) → RT, 52% (15b), 61% (15c), 65% (15d); (h)
[Cp*RuCl]4 (2 mol %), H2 (1 atm), 1,2-dichloroethane, 70 °C, 68%
(NMR, dr = 6:1); (i) 19 (10 mol %), nBu4NCl (12 mol %), H2 (1
atm), 1,2-dichloroethane, 70 °C, 76% (R = TMS); (j) TBAF, THF, 0
°C, 88%; (k) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 89%; (l) nBuLi,
THF, 0 °C, then 18, −78 °C → 0 °C, 78%; (m) 19 (10 mol %),
nBu4NCl (12 mol %), H2 (1 atm), 1,2-dichloroethane, 70 °C, 67%;
(n) TBAF, THF, 0 °C, 97%.
In order to steer the projected carbene formation to the
distal site of the triple bond of enyne 15 and hence ensure that
the envisaged hydrogenative metathesis reaction proceeds with
the desired regioselectivity, the tert-alcohol group must be
protected.34 A priori, different silyl ethers or a SEM-acetal are
adequate for this purpose and should be cleavable after the
event under conditions that are sufficiently mild not to destroy
the elimination-prone tert-alcohol in the resulting products.
Therefore, compound 14a was transformed into 14b-d and
these building blocks then coupled with Weinreb amide 18,
which in turn is available from methyl vinyl ketone by
following a literature route.35
With the three different enynes 15b−d in hand, it was
possible to test the hydrogenative metathesis as the key step of
the synthesis. We were surprised to find that hydrogenation of
the SEM derivative 15b under standard conditions using
[Cp*RuCl]4 as the catalyst furnished only trace amounts of the
desired cyclopentenone; rather, compound 16 formed by C−H
insertion of the transient carbene into the methylene subunit of
the SEM group was the major product. While no such
reactivity had been noticed before for any acetal-protected
model compound,9 this finding prompted us to revisit catalytic
hydrogenative C−H functionalization (see below). The silyl
ether analogues 15c,d were both much better behaved,
especially when complex 19 bearing a less electron rich CpX
ligand was used as the catalyst in combination with nBu4NCl.36
Under these conditions, competing over-reduction was almost
completely suppressed (<5%) and the desired metathesis
products were obtained in 78% and 76% yields, respectively,
despite the crowded situation. The cyclization of the
diastereomeric enyne 17 was similarly productive. Depro-
tection with TBAF furnished sinularones F (10) and E (9), the
C
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NMR spectra of which matched the reported data (for details,
see the Supporting Information).25 Therefore, we conclude
that the assignment of these diastereomeric marine secondary
metabolites, which had been largely based on a comparison of
simulated and recorded spectra,25 is indeed correct.
substrates amenable to gem-hydrogenation.41 As one might
expect, the reaction is highly regioselective in that the
ruthenium carbene I is formed at the internal position. This
regiochemical course likely reflects the hyperconjugation of the
silyl group with the emerging electrophilic carbene center and
predisposes the resulting α-silylated carbene to subsequent 1,2-
silyl migration with the selective formation of alkenylsilanes.41
It was shown that the migratory aptitude of the silyl group is
strongly dependent on the nature of the substituents at silicon
in that one aryl substituent was found necessary to render the
rearrangement facile.41 In consideration thereof, we reasoned
that it should be possible to outperform the 1,2-silyl shift and
engage an α-silylated carbene of type I primarily formed in
productive metathesis or cyclopropanation, depending on the
substitution of the olefin. The examples compiled in Scheme 7
Hydrogenative C−H Insertion. As previously reported,
both hydrogenative metathesis and hydrogenative cyclo-
propanation reactions of several acetal-containing substrates
are high yielding;9 side products derived from competing C−H
functionalization have not been noticed,37 despite the fact that
related piano-stool ruthenium carbenes formed by other means
have previously been used exactly for this purpose.21,38,39 To
explain why C−H insertion interfered with productive
metathesis upon hydrogenation of enyne 15b, we reasoned
that the flanking carbonyl group might play a pivotal role, in
that it renders the transient carbene more highly electrophilic.
Several substrates were made to test this hypothesis
(Scheme 6). Hydrogenations of ynones 20a,b and 23a,b
a
Scheme 7
a
Scheme 6
a
Reagents and conditions: (a) [Cp*RuCl]4 (2 mol %), H2 (1 atm),
b
1,2-dichloroethane, 3 h, 70 °C. The product equilibrates in CDCl3 to
reach this dr after 5 h.
bearing different protecting groups on the propargylic alcohol
substituent under standard conditions all led to C−H insertion
with formation of the corresponding tetrahydrofuran deriva-
tives. The reactions proceed with high diastereoselectivity in
favor of the cis isomers, as deduced from the NMR data; for
24b, the assignment was confirmed by X-ray crystallography
(see the Supporting Information). In contrast, the analogous
ester (25) or amide (26) derivatives failed to afford the
corresponding C−H-insertion products but merely succumbed
to (over)reduction. Computations for substrate 20a suggest
that the insertion reactions proceed via the concerted
transition state H (for details, see the Supporting Informa-
tion); a direct interaction of the carbonyl oxygen atom with the
site of C−H bond cleavage, as previously proposed for related
transformations involving ruthenium carbenes generated by
diazo decomposition,40 does not seem to play a role in this
case.
a
Reagents and conditions: [Cp*RuCl]4 (2 mol %), H2 (1 atm), 1,2-
dichloroethane, 3h, 70 °C. Reagents and conditions in the case of
28b: 19 (20 mol %), nBu4NCl (25 mol %), H2 (1 atm), 1,2-
dichloroethane, 8 h, 70 °C.
show that this is indeed the case. Hydrogenative metathesis
hence opens an entry into variously functionalized allylsilanes.
The hydrogenation of enyne 35 proves that the underlying
concept is not limited to silylated substrates. As expected, the
reaction worked well on a gram scale, as illustrated by the
formation of product 38 (the structure of this compound in
the solid state is contained in the Supporting Information). In
this particular reaction, complex 39 was isolated as a
byproduct, which is presumably formed by oxidative
cyclization of two ynoates followed by reductive elimination
of the resulting ruthenacycle to give the cyclobutadiene
Hydrogenative Metathesis of Enynes without Prop-
argylic Substituents. Silylated alkynes are another class of
D
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ligand.42,43 While this bias is perhaps unsurprising for an
electron-deficient substrate, it constitutes a major catalyst
deactivation pathway because it traps no less than ∼50% of the
initial ruthenium loading. Moreover, the fact that 39 is
obtained as a single regioisomer is deemed highly significant.
The structure of 39 in the solid state (Figure 1) features
surprisingly close contacts between the chloride ligand on
Scheme 8. Examples from the Literature in which the
Reaction Outcome Is Likely Determined by Cl···Si
a
Interactions
a
Reagents and conditions: (a) [Cp*RuCl]4 cat., CH2Cl2 (or
pentane), see ref 47; (b) [Cp*Ru(cod)Cl] cat., neat, see ref 50. •
denotes a CMe edge of the Cp* ring in the Newman projection of the
loaded catalyst and the ensuing ruthenacyclopropene.
Figure 1. Structure of complex 39 in the solid state. Only one of the
two independent molecules in the unit cell is shown, and hydrogen
atoms are omitted for clarity. The green lines indicate attractive
interactions between the polarized [Ru−Cl] bond and the −Si(CH3)3
groups, partially mediated via the hydrogen atoms (cf. the text). For
the full structure, see the Supporting Information.
hydrogenative metathesis as described herein proceeds via
discrete ruthenium carbenes formed by gem-hydrogeantion as
the key reactive intermediates. To this end, enyne 40which
is just one methylene group shorter than the model substrate
1awas hydrogenated with stoichiometric [Cp*RuCl]4 (0.25
equiv) as the precatalyst with the hope of forming a metastable
carbene complex amenable to full characterization (Scheme
9):52 the shortened tether should retard or even prevent
ruthenium and the neighboring silyl groups.44,45 Specifically,
the distances between the −Cl substiuent and the H atoms
directed toward it are all notably short (2.8−3.1 Å; sum of van
der Waals radii: 3.6 Å)46a and likely mediate, at least in part,
the interaction. The Cl1···Si1 (3.43 Å) and Cl1···Si2 (3.56 Å)
distances are also well below the sum of the van der Waals radii
(4.22,46a 3.85 Å46b). Interestingly, they fall into the range
previously computed for an attractive through-space [Ru−
Cl]···Si contact of this type (3.4 Å);48 however, the C−Si−C
angles (average 108.5°) hardly deviate from the ideal
tetrahedral geometry. The 29Si NMR shift might also mirror
the interaction, although this data point cannot be considered
a firm proof (for details, see the Supporting Information).45,48
Under the proviso that attractive interactions of this type are
operative during the upload of the substrate onto the catalyst
and the ensuing transition state leading to the metallacycle, the
head-to-head alignment of the silyl groups in 39 is readily
explained. This observation has implications beyond this
specific case: such interligand interactions had previously been
invoked to explain the regiochemical course of trans-hydro-
silylation reactions of unsymmetrical alkynes (Scheme 8, top)
and related reactions catalyzed by [Cp*RuCl]-based cata-
lysts.47−49 Moreover, they allow an otherwise unexplained
observation reported in the literature to be rationalized: why
the coupling of allyl alcohol with TMS-acetylene on the one
hand and tert-butylacetylene on the other hand proceed at the
opposite end of the triple bond despite the comparable steric
demand (Scheme 8, bottom).50,51 Complex 39 hence
corroborates the notion that interligand interactions involving
a polarized [Ru−Cl] unit are a powerful yet perhaps still
underappreciated control element for different ruthenium-
catalyzed transformations.21a,43,47−49
Scheme 9. Preparation of a Loaded Carbene Complex by
gem-Hydrogenation
intramolecular metathesis from occurring (a strained cyclo-
butene ring would be formed), whereas the bulk in the first
coordination sphere about the metal disfavors competing
intermolecular reactions.
This expectation proved correct in that gem-hydrogenation
of enyne 40 led to the clean formation of an intermediate 41
(≥95%, NMR), which proved stable enough in solution for full
characterization by NMR at low temperature and could even
be isolated in the form of single crystals suitable for X-ray
diffraction.53 The unit cell contains no less than six
independent molecules, and structure elucidation faced an
additional complication of a slight modulation of the structure
along the c unit cell axis in that the individual molecules are
A Loaded Carbene Complex. As a prelude for the
mechanistic studies, we sought rigorous confirmation that
E
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partially replaced by their enantiomers (note that the complex
is chiral-at-metal; for a discussion, see the Supporting
Information); despite these complications, the structural
attributes of the complex in the solid state appear to be
unambiguous (Figure 2). As expected, gem-hydrogenation
substrate; otherwise, “hydrogenative metathesis” transmutes
into an ordinary enyne metathesis with formation of a 1,3-
diene product.12,13
Privileged substrates such as 1a with two methyl groups on
the alkene release 42a as the secondary carbene (Scheme 10).
Scheme 10. Fate of the Secondary Carbene in the Case of an
Enyne Substrate with a Dimethylated Olefin
Figure 2. Structure of one of the six independent molecules of
complex 41 in the solid state. Hydrogen atoms and slight disorder of
Ru1 and Cl1 over two positions are not shown for clarity; for the
entire structure and a brief discussion, see the Supporting
Information.
steered by the −OMe substituent has led to the regioselective
formation of a piano-stool ruthenium carbene at the distal
alkyne C atom. In the resulting 18-electron complex 41, the
tethered olefin, though trisubstituted, has displaced the ether
ligand in complex J, which is thought to be initially formed by
virtue of the steering −OMe substituent. The C4−C5 double
bond is almost orthogonal to the C1−Ru1 carbene unit and
experiences significant back-donation of electron density from
the metal into the empty π* ligand orbital, as manifested in the
elongated C4−C5 bond (1.39(4) Å) and in the fact that the
two methyl substituents (C6, C7) appear slightly out of plane;
both features indicate notable rehybridization of the olefin.
The structure in solution (CD2Cl2) is almost certainly very
similar: only one of the two methyl groups on the olefin shows
a NOE contact with the methyl substituents of the Cp* ligand,
suggesting that the orientation perpendicular to the C1−Ru1
vector observed in the solid state is retained (Scheme 9). The
signal at δC 368.4 ppm confirms the (Fischer) carbene nature
of 41;54 it is actually more deshielded than related half-
sandwich ruthenium carbenes of type J in which the lateral
−OMe substituent remains ligated to the metal center.3,7 The
massive high-field shift of the alkene signals to δC 79.4/79.7
ppm proves that the π system is tightly bound to the metal,
even at ambient temperature, whereas the −OMe is off.55 This
detailed structural portrayal of complex 41 forms a calibration
point for the mechanistic discussion summarized below.
Fate of the Secondary Carbene. The isolation of 41 is
consistent with the hypothesis that [Cp*RuCl] is the
catalytically active species that entails gem-hydrogenation and
is accountable for the conversion of an enyne such as 1a into a
cycloalkene 2a as described herein. The actual metathesis step,
however, generates a secondary carbene of type 42, which
must be reconverted into this active catalyst at a rate that is
faster than its addition to the triple bond of unreacted
We have previously shown that 42a traps free [Cp*RuCl] to
give the binuclear complex 43, held together by two bridging
chloride ligands and the now equally bridging carbene unit
(see the Supporting Information).9,56 43, however, is most
likely a dormant rather than active species, and the turnover-
limiting step likely comes after its formation.9 At elevated
temperatures, which are usually necessary for hydrogenative
metathesis to proceed at a reasonable rate, 43 is in equilibrium
with monomeric 42a: it is this latter species which reacts under
a hydrogen atmosphere via K and L to give propene and
propane, respectively, which represent by far the major
components of the volatile fraction, as confirmed by headspace
GC analysis (see the Supporting Information).9
Alkene Substitution as the Key Determinant. The
representative example depicted in Scheme 2 had shown that
the reaction outcome is critically dependent on the degree of
substitution of the alkene unit of a given substrate. For this
perplexing result, it was also deemed necessary to investigate
the influence of the nature of the substituents. In this context it
is important to note that changes in the substitution pattern do
not only alter the sterics about and electronics of the double
bond to be metathesized or cyclopropanated; in the case of
metathesis, the substituents also profoundly affect the
constitution and stability of the secondary carbene 42, which
must be recycled into the actual catalyst sufficiently quickly.
The examples compiled in Schemes 11 and 12 are relevant
in mechanistic terms. First and foremost, the outcome of the
hydrogenation with [Cp*RuCl] is obviously not a matter of
whether the double bond of the enyne is electron-rich or
electron-deficient. The comparison of substrates 1e with an
F
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a
a
Scheme 11
Scheme 12
a
Reagents and conditions: (a) [Cp*RuCl]4 (2 mol %), H2 (1 atm),
1,2-dichloroethane, 3 h, 70 °C. The color-coded C atom denotes the
more nucleophilic position of the alkene.
Scheme 11 are catalytic processes that proceed well under the
standard conditions outlined above.
The divergent behavior of the difluoroalkene 1f and
compound 1b containing an ordinary terminal olefin is also
informative: because hydrogen and fluorine are not overly
different in size but the outcome of the reactions is opposite,
one must conclude that the product-determining step of the
catalytic cycle is (largely) governed by electronic rather than
steric factors. This notion is corroborated by a comparison of
1a, 1c, and 1d, which shows that disubstitution of the olefin is
also not mandatory. Equally remarkable is the striking switch
observed for enoates 1h and 1i, which differ only in the
presence or absence of a single methyl group: whereas the
former undergoes hydrogenative metathesis to give 2a and just
a trace of what seems to be the corresponding cyclopropane,
the nor-methyl derivative 1i succumbs to clean hydrogenative
cyclopropanation with formation of 3i. The reaction is
stereospecific in that the Z isomer 1j provides the
diastereomeric cyclopropane 3j, which speaks for a highly
ordered selectivity-determining transition state (for details, see
Computational Studies and Mechanistic Discussion). The
compatibility of an aldehyde group as shown by the
hydrogenative conversion of 1k into 3k is yet another
noteworthy aspect.
Additional information can be deduced from the reactions
shown in Scheme 12: although both substrates are enones,
hydrogenation under standard conditions takes an entirely
different course in that 1l furnishes cyclopropane 3l as a single
diastereomer, whereas 1m undergoes metathesis with for-
mation of the cyclopentenone derivative 7.
a
Reagents and conditions: (a) [Cp*RuCl]4 (2 mol %), H2 (1 atm),
1,2-dichloroethane, 3 h, 70 °C; (b) [Cp*RuCl]4 (0.25 equiv), H2 (1
atm), 1,2-dichloroethane, 3 h, RT. The color-coded C atom denotes
the more nucleophilic position of the alkene. The secondary carbenes
are the proposed (catalytic) intermediates, which are shown because
their stability and fate are thought to determine the course of the
overall transformation (metathesis versus cyclopropanation; see the
text). [Ru] = Cp*RuCl.
At first sight, these examples speak for a correlation between
the polarization of the double bond and the reaction outcome.
If one takes the chemical shift as a proxy,61 the trisubstituted
alkene in 1a is more nucleophilic at the internal position,
whereas its cousin 1b is actually more nucleophilic at the
terminus. If thenin accordance with “Markovnikov’s rule”
the prime site of attack of the olefin onto an electrophilic
Fischer-type carbene changes,62 one might assume that 1b
engages in a 6-endo-trig transition state that leads to the
cyclopropane by an outer-sphere process. In contrast, 1a seems
poised for an ordinary Chauvin-type mechanism via a [2 + 2]
cycloaddition/cycloreversion mechanism that ultimately results
in metathesis.12 Under this proviso, one would expect that all
enynes of type 1, in which the position of the alkene proximal
to the ruthenium carbene is the more nucleophilic site, will
undergo metathesis, whereas the opposite polarization results
in cyclopropanation. This model concurs with the fact that the
enol ether and 1f containing a gem-difluoro group at the
terminus illustrates this aspect: though very different in
electronic terms, both substrates undergo metathesis to afford
product 2a. The resulting secondary carbenes 42e,f both carry
heteroatom substituents as stabilizing π-donor ligands;54,57,58
this thermodynamic aspect notwithstanding, the good leaving-
group properties of the heteroelements open low-lying
decomposition pathways which outcompete reconversion
into the propagating species.59 Therefore, a stoichiometric
amount of [Cp*RuCl]4 was necessary to reach full conversion
in both cases; as one might expect, the same is true for the
alkenyl chloride derivative 1g.60 All other reactions shown in
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hydrogenations of substrates 1e and 1f comprising olefins as
different as an enol ether and a difluoroalkene take the same
course and both result in metathesis; likewise, it predicts that
the ordinary terminal alkene 1b and the much more electron
deficient enal 1k both afford the corresponding cyclopropanes.
However, Scheme 11 shows two cases, which cast doubt on
the view that this interpretation assuming a competing outer-
sphere/inner-sphere mechanism captures the full picture.
Specifically, alkenyl chloride 1g and the trisubstituted enoate
1h both show the “distal pattern” yet undergo metathesis (at
least as the major reaction channel).63 In this context, it is also
necessary to re-evaluate the small number of related examples
documented in the literature in which stoichiometric reactions
of preformed Fischer carbene complexes with enynes resulted in
either cyclopropanation or metathesis depending on the
substitution pattern (and/or the solvent).64−66 Fully convinc-
ing explanations have not been published, but it has been
speculated that the stability of the secondary carbene generated
in the case of metathesis might play a role in determining the
reaction outcome. Although this looksa priorilike a
thermodynamic argument, it cannot be discounted in the
first place but deserves further consideration.
Computational Studies and Mechanistic Discussion.
To complement the experimental data and draw a more
accurate picture of the underlying mechanism(s), detailed
computational studies were carried out using DLPNO-
CCSD(T)/def2-TZVPP single-point energies on top of
B3LYP-D3/def2-TZVP(-f) geometry optimization.67−70 The
perturbative triples correction was calculated using the so-
called semicanonical approximation.71 Solvation effects were
included at the DFT level using the implicit solvation model C-
PCM (CH2Cl2).72,73 An initial exploration of the chemical
space74 was carried out using the semiempirical tight-binding
based quantum chemistry method GFN2-xTB.75
Substrates 1a, 1b, 1e, 1f, and 1i were chosen for this
computational survey. First, extensive conformation sampling
showed that in all cases the tethered olefin is η2-ligated to the
Ru center in the most stable carbene complex A formed during
the gem-hydrogenation step, independent of the electronic
character of the double bond. Complexes of type A, as the
starting point for the computations, nicely correspond to
compound 41 characterized by X-ray diffraction (see Figure 2).
The further evolution into the cyclopropane by an outer-
sphere mechanism, as considered in our preliminary
communication with the explicit caveat that more detailed
scrutiny is necessary,9,62 has a prohibitively high activation
barrier (>35 kcal mol−1) and can hence be safely disregarded.
Rather, A first converts into a “kite-shaped” metallacycle A′
before the pathway bifurcates, in which all three C atoms
entertain bonding interactions to the metal (Figure 3).
Depending on the specific substitution pattern, A′ is either a
regular minimum on the potential energy surface or just an
“inflection point”, as in the case of enyne 1b with the terminal
alkene shown in Figure 3.76 This distorted metallacycle A′ can
cyclorevert via TSAB to afford the (invariant) metathesis
product C and the corresponding secondary carbene;
alternatively, it can evolve via TSAD into the “regular”
metallacycle D, which undergoes reductive elimination and
releases cyclopropane F (this step is facilitated by agostic
interactions in the transition state TSDE and the resulting
adduct complex E).77 For enyne 1b with the terminal alkene,
TSAD leading to the cyclopropane is 1.9 kcal mol−1 lower in
Gibbs free energy than TSAB en route to the metathesis
Figure 3. Metathesis versus cyclopropanation pathways for a carbene
complex derived from enyne 1b with a terminal alkene; as a reference
energy we used the substrate and the [Cp*RuCl] catalyst. For the
sake of simplicity, only the key intermediates and transition states
along the minimum energy pathways are shown.
product; this computational result is in excellent agreement
with the experimentally observed outcome.78 For the highly
ordered character of the transition state leading to D and of the
subsequent reductive elimination step, it is readily understood
why cyclopropanation reactions of substituted alkenes proceed
stereospecifically (compare 1i and 1j in Scheme 11; additional
examples are contained in ref 9).
This basic scenario remains the same for all substrates
investigated (1a, 1b, 1e, 1f, and 1i), but the substituents at the
alkene terminus and the electronic character of the alkene
massively affect the barrier heights. The case of the “isosteric”
difluoroalkene derivative 1f is representative (Figure 4; for the
other cases, see the Supporting Information): the distorted
metallacycle A′(f) formed before the pathways bifurcate is a
true intermediate rather than an inflection point. Once it is
reached, metathesis is almost barrierless and outcompetes
cyclopropanation; this computed outcome is again in accord
with experiment.
It is significant that the barriers for cyclopropanation are
fairly “insensitive” even for enynes comprising olefins as
different as a terminal and a difluorinated alkene (15.9 and
10.6 kcal mol−1, respectively).79 In striking contrast, the
barriers for metathesis are massively affected in that ΔG⧧
decreases from 17.8 kcal mol−1 for 1b to only 2.3 kcal mol−1
for 1f. The trend that the barrier for cycloreversion of the
distorted metallacycle and hence metathesis is particularly
responsive to changes of the substitution pattern and/or
polarization of the olefin (as manifested in the NPA charges)
pertains to all substrates investigated (Table 1): in essence, it is
this effect that determines the outcome.80
This computational result warrants further consideration, as
does that fact that the path leading to the cyclopropane passes
through two distinctly different metallacycles, whereas meta-
thesis involves only one. It is well established in the literature
that metallacyclobutanes in general fall into two different
categories (Figure 5).81−83 One type features a significant
agostic interaction between the metal and the Cβ atom, which
in turn results in a short M···Cβ contact, weakened Cα−Cβ
H
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Figure 4. Metathesis versus cyclopropanation pathways for a carbene
complex derived from enyne 1f with a difluoroalkene moiety; as a
reference energy, we used the substrate and the [Cp*RuCl] catalyst.
bonds, and notable alkylidene character at Cα/Cα′; metalla-
cycles of this sort are prone to cycloreversion. The other type
of metallacyclobutanes, in contrast, lacks the M···Cβ agostic
interaction and the other characteristics that it entails; most
notably, their Cα atoms do not have any significant alkylidene
character. Intermediates of this latter type easily succumb to β-
H-elimination reactions or reductive elimination.
Figure 5 depicts the computed ruthenacyclobutane sub-
structure of complexes A′(b) and D(b) derived from enyne 1b.
From the overall geometries and metric data it is obvious that
they correspond very well to the two extremes: for the “kite-
shaped” metallacycle A′(b) to transform into D(b), it must
undergo a change in bonding (loss of the β-agostic interaction)
accompanied by a significant change in geometry, which
actually brings the Cα/Cα′ atoms closer together (for further
details, see the Supporting Information). Only after D(b) is
reached can reductive elimination with formation of the
cyclopropane occur. It is intuitive that any substitution pattern
on the ring that increases the alkylidene character of the Ru−
Cα bond of A′(b) will disfavor this process relative to [2 + 2]
Figure 5. Computed structures of the ruthenacyclobutane entites of
complexes A′(b) (top) and D(b) (bottom) derived from enyne 1b
with the terminal alkene. Distances are given in Å.
cycloreversion: a π-donor substituent and/or an appropriately
polarized double bond fall into this category.54−57
It is equally important to recognize that a (heteroelement)
substituent at Cα that increases the carbene (alkylidene)
character of the metallacycle A′ and therefore favors metathesis
also translates into the thermodynamically more stable
secondary carbene 42. The significant lowering of the barrier
heights of TSAB on the metathesis pathway can hence be seen
as an illustration of the Bell−Evans−Polanyi principle, which
a
Table 1. Computed Barriers That Determine the Evolution of the Ruthenium Carbene Complex A Primarily Formed
Q
outcome
b
c
d
ΔG⧧(TSAB
)
ΔG⧧(TSAD
)
ΔG(A→C)
substrate
terminus
at C1
at C2
(kcal mol−1
)
(kcal mol−1
)
(kcal mol−1
)
predicted
exptl
1b
1i
1a
1f
−CHCH2
−0.39
−0.32
+0.02
+0.72
+0.12
−0.17
−0.08
−0.20
−0.36
−0.28
17.8
21.4
10.8
2.3
15.9
11.2
21.6
10.6
15.5
+5.8
+6.6
−4.1
−12.7
−7.7
cycloprop
cycloprop
metathesis
metathesis
metathesis
cycloprop
cycloprop
metathesis
metathesis
metathesis
−CHCHCOOEt
−CHCMe2
−CHCF2
1e
−CHCH(OMe)
3.7
a
b
Q denotes the NPA (natural population analysis) charge at the “terminal” (C1) and internal (C2) atom of the olefin. TSAB refers to the
c
cycloreversion step and hence the reaction channel resulting in metathesis. TSAD is the first transition state toward cyclopropanation, which may or
may not be the highest barrier of this pathway; see the Supporting Information. Thermochemistry associated with the transformation of the
d
primary carbene into the metathesis product 2a together with the corresponding secondary carbene (C).
I
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links the energy of the transition state to the energy of the
subsequent intermediate (Figure 6).84 Since all hydrogenations
largely determined by the substitution pattern of the olefin,
which is a perplexing result at first sight. A systematic
investigation in combination with computational study allowed
the seemingly bewildering results to be sorted and an intuitive
model to be deduced, which allows the course of the reaction
to be predicted on the basis of the substitution pattern of the
substrate. The computational data find excellent correspond-
ence in a half-sandwich carbene complex, in which the olefinic
partner is coordinated to the ruthenium center, which
represents the “loaded” catalyst and which was fully
characterized by spectroscopic and crystallographic means. A
first application to the total synthesis of two diastereomeric
marine natural products illustrates the virtues of this
methodology, as does a new hydrogenative entry into
allylsilanes, which are valuable building blocks in organic
synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
sı
(PDF) Copies of (PDF) Crystallographic data (CIF) The
Supporting Information is available free of charge at https://
pubs.acs.org/doi/10.1021/jacs.0c07808.
Experimental section containing supporting X-ray
structures and crystallographic information, character-
ization data, and computational details (PDF)
NMR spectra of new compounds (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Figure 6. Illustration of the Bell−Evans−Polanyi principle. The
barrier height for cycloreversion (ΔG⧧(TSAB)) correlates with the
stability of the secondary carbene complex released together with the
invariant metathesis product ((ΔG(A → C)): a more exergonic
cycloreversion process exhibits a lower activation barrier (the energies
relative to the initial carbene complex A).
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
shown in Scheme 11 form the same metathesis product 2a, it is
the stability of the secondary carbene 42a−k which makes the
key difference because it manifests itself already in the
transition state: in cases in which the secondary carbene is
destabilized (shaded in gray), TSAB is expected to be high in
energy and metathesis is hence prevented.
AUTHOR INFORMATION
Corresponding Author
■
Alois Fu
45470 Mu
0098-3417; Email: fuerstner@kofo.mpg.de
̈
rstner − Max-Planck-Institut fu
̈
r Kohlenforschung,
̈
lheim/Ruhr, Germany; orcid.org/0000-0003-
In a view through this lens, one may conclude that the
original proposals made in the literature that the polarization of
the double bond of the substrate or the stability of the
secondary carbene determines the course of the reaction are
both correct in a way, even though it took the computations to
understand why that is the case. The insight that the Bell−
Evans−Polanyi principle intimately connects the substitution
pattern with the critically responsive barrier height of the
metathesis pathway results in a rather intuitive model based on
an assessment of the substrate’s ground state, which allows the
outcome of the reactions to be predicted with confidence; it
forms a sound basis that should encourage the practitioners to
implement gem-hydrogenations into increasingly complex
settings. In any case, ongoing work in this laboratory intends
to widen the scope of this unusual novel entry into the realm of
transition-metal carbenes and to refine our understanding of
the underlying principles.
Authors
Sebastian Peil − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany
Giovanni Bistoni − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0003-
4849-1323
Richard Goddard − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0003-
0357-3173
̈
r Kohlenforschung,
̈
̈
r Kohlenforschung,
̈
̈
r Kohlenforschung,
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07808
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
CONCLUSIONS
■
■
The gem-hydrogenation of internal alkynes is a fundamentally
new transformation that gives access to discrete metal carbene
complexes for use in synthesis. For substrates that contain a
tethered alkene, the piano-stool carbene intermediates derived
from [Cp*RuCl] as the privileged catalyst can undergo
cyclopropanation or metathesis reactions. The outcome is
Generous financial support by the MPG is gratefully
acknowledged. We thank Dr. A. Guthertz and Mr. T. Biberger
for early experimental contributions and discussions and all
analytical departments of our Institute for valuable support,
especially Mr. J. Rust and Prof. C. W. Lehmann, for excellent
X-ray service.
J
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799−801.
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