Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes

Article abstract of DOI:10.1021/jacs.8b00665

The hydrogenation of internal alkynes with [Cp?Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H₂. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (??²-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a ?€-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H₂ molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H₂, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic aOR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem-hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions.

Full text of DOI:10.1021/jacs.8b00665

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Article
Half-Sandwich Ruthenium Carbene Complexes Link trans-
Hydrogenation and gem-Hydrogenation of Internal Alkynes
Alexandre Guthertz, Markus Leutzsch, Lawrence M. Wolf, Puneet Gupta, Stephan
M. Rummelt, Richard Goddard, Christophe Farès, Walter Thiel, and Alois Fürstner
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00665 • Publication Date (Web): 11 Feb 2018
Downloaded from http://pubs.acs.org on February 11, 2018
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Half-Sandwich Ruthenium Carbene Complexes Link trans-
Hydrogenation and gem-Hydrogenation of Internal Alkynes
Alexandre Guthertz, Markus Leutzsch, Lawrence M. Wolf,† Puneet Gupta, Stephan M. Rummelt, Richꢀ
ard Goddard, Christophe Farès, Walter Thiel, and Alois Fürstner*
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MaxꢀPlanckꢀInstitut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany
ABSTRACT: The hydrogenation of internal alkynes with [Cp*Ru]ꢀbased catalysts is distinguished by an unorthodox stereochemiꢀ
cal course in that Eꢀalkenes are formed by transꢀdelivery of the two Hꢀatoms of H2. A combined experimental and computational
study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2ꢀvinyl complex) is primarily formed which
either evolves into the Eꢀalkene via a concerted process or reacts to give a halfꢀsandwich ruthenium carbene; in this case, one of the
Cꢀatoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gemꢀhydrogenation of a
πꢀbond, which has hardly any precedent. The barriers for transꢀhydrogenation and gemꢀhydrogenation are similar: whereas DFT
predicts a preference for transꢀhydrogenation, CCSD(T) finds gemꢀhydrogenation slightly more facile. The carbene, once formed,
will bind a second H2 molecule and evolve to the desired Eꢀalkene, a positional alkene isomer or the corresponding alkane; this
associative pathway explains why double bond isomerization and overꢀreduction compete with transꢀhydrogenation. The computed
scenario concurs with paraꢀhydrogen induced polarization transfer (PHIP) NMR data, which confirm direct transꢀdelivery of H2,
the formation of carbene intermediates by gemꢀhydrogenation, and their evolution into product and side products alike. Propargylic
–OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated
and characterized by Xꢀray diffraction. The gathered information spurred significant preparative advances: specifically, highly
selective transꢀhydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional
groups. Moreover, the ability to generate metal carbenes by gemꢀhydrogenation paved the way for nonꢀcanonical hydrogenative
cyclopropanations, ring expansions and cycloadditions.
INTRODUCTION
applications to compounds containing other reducible and/or
baseꢀsensitive functionality are precluded.
Canonical hydrogenations of πꢀbonds with the aid of transiꢀ
tion metal catalysts − as long as they do not involve transfer of
H• − are under frontier orbital control.1ꢀ3 As a consequence,
they invariably proceed via suprafacial delivery of the two
hydrogen atoms of H2 to the substrate. In view of this stringent
synꢀselective course, it is unsurprising that a considerable
number of heterogeneous as well as homogeneous catalysts is
known that allow internal alkynes to be semiꢀhydrogenated
with formation of the corresponding (Z)ꢀalkenes; among them,
Lindlar hydrogenation is arguably the most popular protocol.4ꢀ
6 Although the individual methods greatly differ in efficiency
and practicality as well as in their bias to saturate the olefin
products initially formed, the stereoselectivity is generally
excellent. If overꢀreduction prevails or other reducible sites are
endangered under hydrogenation conditions, alternative stoiꢀ
chiometric procedures are available to the practitioner that also
allow alkynes to be transformed into (Z)ꢀolefins with appreꢀ
ciable selectivity.7,8
A few methods for formal transꢀhydrogenation (or transfer
hydrogenations) of alkynes are known.15,16 In mechanistic
terms, however, these reactions commence with a canonical
cisꢀreduction followed by Z→E isomerization; for this latter
step to proceed well, the double bond usually has to carry at
least one aryl substituent or must be significantly polarized.
Therefore, none of the methods falling into this category
shows any decent scope when it comes to the semiꢀreduction
of ordinary dialkylalkynes.
The arguably best current alternative is an indirect proceꢀ
dure in which the alkyne is first subjected to a rutheniumꢀ
catalyzed transꢀhydrosilylation, as originally described by
Trost and coworkers,15,17,18 followed by desilylation of the
resulting alkenylsilane with the help of a mild fluoride
source.17,19 For its excellent selectivity profile and broad
scope, this twoꢀstep protocol was rapidly embraced by the
synthetic community;20,21 it finds its limitations when it comes
to the transꢀhydrosilylation of sterically hindered substrates or
compounds comprising conjugated πꢀsystems such as 1,3ꢀ
enynes; products sensitive to fluoride are typically also beyond
reach.22
The situation is much less comfortable when it comes to the
semiꢀreduction of internal alkynes to the corresponding (E)ꢀ
alkenes. The classical arsenal is basically limited to dissolving
metal reductions;9 other reagents capable of transferring elecꢀ
trons to triple bonds such as Cr(+2) have occasionally been
used for the same purpose.10 Moreover, LiAlH4 or related
metal hydrides allow propargyl alcohols (and very few other
substrates)11 to be converted to the corresponding Eꢀ
configured allylic alcohols.12ꢀ14 The use of alkali metals in
liquid ammonia or of highly reactive aluminum hydrides,
however, drastically limits the scope of these methods since
Our laboratory has recently demonstrated that transꢀ
hydrosilylation is by no means a singularity but only one of
several possible incarnations of an unorthodox but certainly
more general mechanism. The underlying concept has been
successfully translated into widely applicable transꢀ
hydroboration,23 transꢀhydrogermylation24,25 and transꢀ
hydrostannation reactions.24,26,27 These transformations are
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distinguished by excellent chemoꢀ and stereoselectivity and Similar issues have been noticed with a number of model
can be controlled in regiochemical terms in many cases,24,27 as
witnessed by a growing number of applications to natural
product synthesis.28,29 Moreover, direct transꢀhydrogenation of
internal alkynes has been accomplished, which truly violates
the paradigm of suprafacial delivery of H2 that had been reignꢀ
ing catalytic hydrogenation ever since its inception.30 Thus,
cationic as well as neutral [Cp*Ru]ꢀbased complexes allow
triple bonds to be semiꢀhydrogenated to the corresponding Eꢀ
alkenes with impeccable transꢀselectivity; there is no indicaꢀ
tion whatsoever that the net outcome might be the result of
compounds.30 Interestingly, these studies suggested that overꢀ
reduction and isomerization are not primarily caused by secꢀ
ondary processes in which the product alkene reacts further
with the catalyst. If substantial amounts of such byꢀproducts
are formed, as in the brefeldin case, they seem to be largely
generated in situ. To clarify this opaque yet important aspect,
we embarked into a combined experimental/theoretical study
of this unconventional alkyne transꢀhydrogenation reaction,
which led to a fairly concise picture. During this investigation,
it also became clear that its nonꢀcanonical mechanism proꢀ
vides additional opportunities beyond hydrogenation, as outꢀ
lined in the following summary of our work in this field.35
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classical cisꢀreduction followed by Z
→E isomerization of the
primary product; dialkyl alkynes are hence adequate if not
even the preferred substrates.31 In mechanistic terms, this
method is different from the procedures mentioned above:16 it
represents a true stereochemical complement to the classical
Lindlarꢀhydrogenation and constitutes a potentially attractive
alternative to dissolving metal reductions, in particular when it
comes to applications to functionalized substrates.32
RESULTS AND DISCUSSION
NMR Spectroscopy. Preliminary NMRꢀinvestigations that
made use of the remarkable sensitivity of paraꢀhydrogen (pꢀ
H2) induced polarization transfer (PHIP)36ꢀ39 had shown that
the (E)ꢀalkene formed by semiꢀhydrogenation of a representaꢀ
tive alkyne such as 4a exhibits PHIPꢀenhanced olefinic signals
1
Scheme 1. Alkyne trans-Hydrogenation and Competing
in the H NMR spectra (Figure 1). This result proves that the
Isomerization en route to Brefeldin A
Hꢀatoms of H2 are transferred in a pairwise manner to the
substrate.35 Surprisingly, PHIPꢀenhanced signals were also
observed in the aliphatic region of the spectra, which fade
away once full conversion is reached. These resonances
showed large negative scalar coupling constants of −15 to −19
Hz (or even larger, see below), suggestive of the presence of
geminally coupled diastereotopic methylene protons. Furtherꢀ
more, it was observed that RO− substituents (R = H, Me) next
to the triple bond increase the lifetime of these transient speꢀ
cies;35 actually, substrates of type 8 bearing two stabilizing
groups furnished intermediates with a sufficiently long lifeꢀ
time to allow for full characterization by conventional NMR
(Figures 2 and 3). The data – not least the signature high freꢀ
quency signals in the 13C NMR spectra − left no doubt about
the carbene nature of these intermediates. This assignment was
confirmed when we managed to grow crystals of complex 9b
suitable for Xꢀray diffraction.35 The structure in the solid state
showed the presence of a pianoꢀstool ruthenium carbene unit
and revealed how the neighboring −OR groups exert their
stabilizing influence: the −OMe group engages in a doꢀ
nor/acceptor interaction with the Lewisꢀacidic metal center,
whereas the −OH substituent entertains a hydrogen bond with
the −Cl ligand on ruthenium.40
These aspects are illustrated by a total synthesis of brefeldin
A, a macrolide of fungal origin that selectively targets the
Golgi apparatus of eukaryotic cells (Scheme 1).33 Specifically,
cycloalkyne 1 formed by ring closing alkyne metathesis34 was
hydrogenated on a gram scale to give product 2 with an E:Z
ratio approaching the limits of detection (>99:1). The reduciꢀ
ble enoate, the lactone and the silyl ether passed uncomproꢀ
mised; this ensemble of functional groups would certainly not
subsist under Birch conditions, had an alkali metal in liquid
ammonia been used as the reducing agent. These virtues notꢀ
withstanding, the brefeldin case also illustrates the currently
most prominent shortcoming of this emerging methodology:
with [Cp*Ru(cod)Cl] as the precatalyst, substantial overꢀ
The fact that an alkyne is transformed into a carbene upon
hydrogenation is remarkable in conceptual terms. In a formal
sense, the triple bond behaves as a 1,2ꢀdicarbene synthon:41
one “carbene” center is intercepted by the [Cp*Ru] fragment,
whereas the vicinal “carbene” site oxidatively inserts into the
H−H bond. The resulting net geminal hydrogenation has hardꢀ
ly any precedent in the literature.42 While largely unknown for
carbon, geminal hydrogen delivery is the prototypical reactiviꢀ
ty mode of transition metal centers when exposed to H2.43
reduction
was
noticed,
whereas
the
use
of
[Cp*Ru(MeCN)3]PF6 led to partial positional isomerization of
the disubstituted double bond to the trisubstituted position at
the ring junction (3a) or endocyclic to the fiveꢀmembered ring
(3b). Therefore the desired product 2 was isolated only in 56%
yield.33
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H2 using [Cp*Ru(cod)Cl] as the catalyst showing the cross
1
2
peaks between the gemꢀhydrogen atoms and the lowꢀfield
carbene resonance of 9a
3
4
5
Table 1. Effect of Propargylic Heteroatom Substituents on
the Carbene Distribution as Determined by NMR
6
7
8
9
10
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Substrate R1
R2
[Ru]
6:7[a]
4a
H
Me
[Cp*Ru(cod)Cl]
[Cp*Ru(MeCN)3]PF6
[Cp*Ru(cod)Cl]
[Cp*Ru(MeCN)3]PF6
[Cp*Ru(cod)Cl]
[Cp*RuCl]4
1:10
2:3
4b
Me
Me
1:99
1:14
5:2
4c
4d
4e
H
Et
Me
H
Ph
tBu
1:3[b]
99:1
1:1
[Cp*Ru(cod)Cl]
[Cp*Ru(MeCN)3]PF6
4f
Me
tBu
[Cp*RuCl]4
ꢀꢀꢀ [c]
Figure 1. Hydrogenation of 4a with pꢀH2 catalyzed by
[a]
[b]
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[Cp*RuCl] primarily affords three products showing hyperpoꢀ
larized antiphase signals; whereas the vicinal coupling of the
olefinic protons of 5a is positive, the coupling constants of the
geminal protons of the transient carbene intermediates 6a and
7a have a negative sign
PHIP data, unless stated otherwise; determined by standꢀ
ard 1H NMR; [c] no carbene formation observed, see Text
The results compiled in Table 1 provide further insights into
the directing effect exerted by propargylic substituents. It is
evident that (i) a propargylic −OMe group is a more effective
guide than the corresponding free alcohol, (ii) carbenes deꢀ
rived from a neutral [Cp*RuCl] fragment are more responsive
than their congeners derived from the cationic precatalyst
[Cp*Ru(MeCN)3]PF6, and (iii) the directing effect exerted by
a chelating substituent may be reinforced or counterbalanced
by steric factors. The selective formation of compound 6e
from 4e and [Cp*Ru(cod)Cl], for example, suggests that an
attractive −OH⋅⋅⋅Cl interaction synergizes with the steric reꢀ
pulsion between the bulky Cp* ligand and the lateral tertꢀbutyl
group (see Figure 7 below). The corresponding methyl ether 4f
was the only substrate of this series that failed to undergo
hydrogenation; neither formation of the corresponding Eꢀ
alkene nor of any intermediate (alkyne πꢀcomplex, carbene)
was observed, likely for steric reasons. Though unsurprising in
view of the bulk of the ancillary Cp* ligand on the catalyst,
this outcome indicates that the current methodology finds a
limitation when it comes to reductions of substrates that are
overcrowded on either alkyne terminus.
Figure 2. Spectral features of a set of ruthenium carbenes 9
prepared by gemꢀhydrogenation of substrates of type 8
An additional series of NMR experiments was meant to
clarify whether neighboring –OR substituents are mandatory
to engender formation of carbene species. NMRꢀmonitoring of
the hydrogenation of unfunctionalized substrates such as 2ꢀ
pentyne or 3ꢀhexyne with pꢀH2 showed rapid formation of the
corresponding Eꢀalkenes but did not allow any carbene interꢀ
mediate to be observed; it could not be decided experimentalꢀ
ly, however, whether such an intermediate is not formed or if
it is simply too short lived to be detected.44 Yet, the computaꢀ
tional data outlined below leave no doubt that unfunctionalꢀ
ized substrates are equally capable of forming metal carbenes
in the first place by gemꢀhydrogen delivery.
δ
δ
δ
δ
δ
(1H) / ppm
Hydrogenations of ynoates and ynones with pꢀH2 definitely
involve transient carbene intermediates; a representative exꢀ
ample is shown in Figure 4. In this case, the J coupling conꢀ
1
Figure 3. Excerpt of the H/13CꢀHMBC spectrum of the reacꢀ
tion mixture formed upon hydrogenation of 8a (R = H) with pꢀ
2
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the solvent for 18 h, which led to the saturated compound 15
stant is remarkably large (−24.3 Hz): this conspicuous spectral
feature indicates the presence of a fiveꢀmembered ring,45
which in turn implies that the metal carbene resides distal to
the carbonyl and the oxygen atom is ligated to ruthenium
(10A); this positioning follows and enhances the natural polarꢀ
ization of the 2ꢀdecyneꢀ4ꢀone substrate. Although one might
expect that chelation to a Lewisꢀacidic metal center favors
enolization of the carbonyl, the recorded PHIPꢀdata rule out
that ynoateꢀ or ynoneꢀderived carbenes have ground state
1
2
3
4
5
6
7
8
as the only product. In contrast, formation of 12b (R = H) and
further evolution into the Eꢀalkene 14 could not be decoupled
even at ambient temperature. This comparison shows that a
propargyl ether exerts a stronger stabilizing effect onto the
emerging carbene than a propargyl alcohol or a ketone carꢀ
bonyl group.
4
Scheme 2. Assessing the Stabilizing Effect of Propargylic
−OR Groups (R = H, Me)
structures of type 10B, for which small J coupling constants
9
are expected; moreover, the OPSY spectra lack any signals
that could be attributed to an “enol” substructure (for details,
see the SI).46
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Cl
R1O
R1O [Ru]
R1 = H
RT
Ru
[Cp*RuCl]4
H2, CD2Cl2
HO
O
11
12
15
13
O
O
H2, DCE, 70°C
60%
R1 = Me
MeO
a
b
R1 = Me
R1 = H
not:
HO
H
Ru
R1
O
Ru
R1
Cl
O
Cl
R2
R2
14
O
O
H
H
H
2
10A
( JH,H = -24.3 Hz)
10B
2 .6 0
2 .5 0
2 .4 0
Figure 4. gemꢀHydrogenation of ynones leads to carbene
chelate complexes of type 10 distinguished by a particularly
2
large J coupling constant; this distinctive spectral feature is
shown for R1 = Me, R2 = C6H13; for further details, see the SI
Qualitatively, the data outlined above leave no doubt about
the intervention of ruthenium carbenes generated by formal
gemꢀhydrogenation. The concentration of such intermediates
in solution, however, is almost certainly highly variable and
strongly substrateꢀdependent. Because the intensities of sigꢀ
nals with and without PHIPꢀeffect cannot be directly comꢀ
pared, an accurate quantitative assessment was not possible in
most cases reported herein. Moreover, the recorded spectra
represent only snapshots which depend on the currently unꢀ
known rate of carbene formation/consumption relative to the
NMR timescale. These caveats notwithstanding, it is of note
Figure 5. Structure of the alkene complex 13 in the solid state;
the two independent molecules present in the unit cell are
mutually linked via intermolecular −OH⋅⋅⋅Cl−Ru H−bonds
(see the SI); only the olefinic and –OH protons are shown for
clarity
1
that the antiphase signal intensities observed in routine H
NMR spectra were lower than the ordinary proton signals of
substrate and/or product in a number of cases; if so, the conꢀ
centration of the metal carbene transiently formed must be
very small. The hydrogenation of 2ꢀdecyneꢀ4ꢀone leading to
carbene 10A is representative (for details, see the SI). Yet, we
also noted the other extreme marked by ruthenium carbenes
such as 6e, 7d or 12a which enjoy efficient stabilization by
lateral heteroatom substituents within a sterically favorable
microenvironment; these complexes were formed almost
quantitatively as judged by 1H and 13C NMR (see the SI).
Decomplexation of the catalyst from product 14 was found
to be slow enough such that adduct 13 primarily formed could
be detected and even isolated in pure form (Figure 5). This
observation was unexpected since a recent investigation on the
mechanistically related transꢀhydrostannation of alkynes had
shown that product release from the active catalyst is extremeꢀ
ly facile even at low temperature.27 In complex 13, it is the
alcohol oxygen rather than the carbonyl that coordinates onto
the Lewisꢀacidic ruthenium center and, in doing so, helps to
keep the olefinic ligand in place; the −OH proton engages in
tight intermolecular hydrogen bonding (2.17/2.28 Å) to the Cl
atom of the second independent molecule present in the unit
cell. Moreover, the lowꢀlying π*ꢀorbital of the enone favors
electron backꢀdonation from the metal center, as manifest in
the notably elongated C4−C5 alkene unit (av. 1.408(4) Å).47
Substrates 11a,b were designed to compare the steering efꢀ
fect exerted by a carbonyl and a propargylic –OR substituent
(Scheme 2). For either substrate, the highly regioselective
formation of a carbene intermediate of type 12 was observed
by NMR, in which the [Cp*Ru=C] unit resides distal to the
−OR group but vicinal to the ketone; this conclusion was
confirmed by crystallographic means (see Figure 9 below).
The regioselective course is noteworthy as it shows that the
directing capability of a −OR group outweighs the effect exꢀ
erted by a ketone. 12a (R = Me) proved considerably more
stable that its congener 12b (R = H): for 12a to react further,
the mixture had to be stirred at 70°C in 1,2ꢀdichloroethane as
Relevance of the Carbene Intermediates for Catalysis.
Collectively, the data outlined above show that heteroatom
substituents in proximity to the triple bond to be hydrogenated
steer the regiochemical course of carbene formation and masꢀ
sively impact their lifetime. This raised the crucial question as
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to whether metaꢀstable carbenes such as 6, 7, 9, 10 or 12 have
any relevance for alkyne transꢀhydrogenations or if they are
1
2
nothing but unreactive sinks off the catalytic cycle.
3
4
5
O
O
O
6
7
H
H
H
H
H
H
H
16
5b
17
8
9
1.7
1.8
1.9
10
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Cl
O
Ru
2.5
2.6
2.7
H
7b
H
Figure 7. Structure of one of two independent carbene comꢀ
plexes 6e present in the unit cell; only the Hꢀatoms delivered
by gemꢀhydrogen transfer are shown; for the strong hydrogen
bond (ca. 2.40 Å) between the –OH group and the −Cl of a
neighboring molecule in the crystal, see the SI.
4.60
2.20
1.40 1.35
5.35
5.25
Figure 6. Relevant strips of the 2D 1HꢀOPSYꢀEXSY spectrum
(CD2Cl2, 298 K, ppm) showing cross peaks which link carbene
7b formed by hydrogenation of 4b (R = Me) with pꢀH2 in the
presence of [Cp*Ru(cod)Cl] with the Eꢀalkene 5b, the posiꢀ
tional alkene isomer 16, the overꢀreduced product 17 as well
as H2.
1
To clarify this critically important aspect, a 2D HꢀOPSYꢀ
EXSY experiment48,49 was carried out in which compound 4b
(R = Me) was hydrogenated with pꢀH2 using [Cp*Ru(cod)Cl]
as the precatalyst (Figure 6).50 Because of the high sensitivity
of this hyperpolarization method, the exchange experiment
unmistakably showed that the characteristic methylene signals
of the carbene 7b generated in situ has cross peaks with resoꢀ
nances of the desired Eꢀalkene product 5b,51 the positional
isomer 16, the saturated compound 17 as well as free hydroꢀ
gen in solution. Importantly, this result proves that carbene 7b
is linked to product and sideꢀproducts alike; it is therefore on
the productive cycle (or at least connected to it), yet also
seems to be a gateway to the undesirable overꢀreduction prodꢀ
uct and alkene isomer.
Figure 8. Structure of complex 7d in the solid state; only the
Hꢀatoms delivered by gemꢀhydrogen transfer are shown.
Carbene Structures in the Solid State. NMR suggested
that carbene complexes 6e, 7d, 12a are generated almost quanꢀ
titatively and might be sufficiently stable to allow for isolation
in pure form. After considerable experimentation, we indeed
managed to grow single crystals of these sensitive species
suitable for Xꢀray diffraction.
The structure of 6e in the solid state (Figure 7) is comparaꢀ
ble to the structure of complex 9b previously communicated,35
even though it comprises only a single stabilizing −OH subꢀ
stituent. The carbene resides adjacent to the tertiary alcohol,
which engages directly with the Ru atom as evident from the
short O1−Ru1 distance (2.234(3) Å) to give a complex with a
formal 18e count. In the crystal, the −OH group entertains an
additional strong hydrogen bonding interaction with the chloꢀ
ride of a neighboring molecule (ca. 2.40 Å).40
Figure 9. Structure of the carbene 12a in the solid state; only
the Hꢀatoms delivered by gemꢀhydrogen transfer are shown
The structural features of complexes 7d and 12a are also inꢀ
formative (Figures 8 and 9). In line with the notion that methyl
ethers exert a strong directing effect, the donor/acceptor interꢀ
action O1−Ru1 (2.217(1) Å in 7d; 2.187(3) Å in 12a) is shortꢀ
er that the corresponding contact of the free alcohol in 6e (av.
2.234(3) Å) which is part of a fourꢀmembered ring.
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The lengths of the carbene units in 6e (av. 1.892(2) Å), 7d
(1.906(2) Å), 9b (av. 1.889(7) Å)35 and 12a (C1−Ru1 1.897(4)
Å) are all similar. Although they are slightly longer than the
Ru=CHPh bond of prototype Grubbs carbenes (1.79ꢀ1.85
Å),52,53 backbonding from the metal into the carbene LUMO is
likely significant. This notion is corroborated by the fact that
the phenyl ring in 7d is not coplanar with the carbene unit
(Ru1−C1−C10−C15 39.8°); this feature distinguishes the
ruthenium carbenes discussed herein from related gold or
rhodium carbene complexes, in which overlap of the “empty”
carbene pꢀorbital with the πꢀbonds of the flanking aryl rings
rather than dπ→pπ backꢀbonding is the prime stabilizing facꢀ
tor.54
Scheme 4. The Free Energy Profile Bifurcates at the
Metallacyclopropene Stage between Direct trans-
Reduction and Formation of a Ruthenium Carbene
1
2
3
4
5
6
7
8
9
10
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12
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16
17
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52
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58
59
60
The torsional angle O2−C10−C1−Ru1 of −95.5° in complex
12a implies little orbital overlap between the electrophilic
carbene center and the equally electrophilic ketone Cꢀatom in
the solid state. Whether or not this electronic decoupling perꢀ
sists in solution needs further scrutiny: we note that the 13C
NMR resonance of the carbene center in 12a (δC = 295.5 ppm)
is shifted to lower frequency compared with the resonances in
the sister compounds 6e (δC = 306.3 ppm) 7d (δC = 305.2
ppm) and 9b (δC = 340.9 ppm);35 since the adjacent ketone is
markedly deshielded (δC = 223 ppm), some mutual influence
between these sites in solution is likely.
Scheme 5. An Associative Mechanism Links the Rutheni-
um Carbene to the Side Products
DFT Study Using a Model Substrate. A detailed computaꢀ
tional study was carried out for the sake of a better underꢀ
standing of the mechanism of this unorthodox transꢀ
hydrogenation reaction in general, the origins of the high
stereoselectivity and the role of the carbene intermediates. To
this end, free energy profiles were computed at the M06/def2ꢀ
TZVP level for all putative reaction pathways including those
leading to olefin isomerization or overꢀreduction (see Supportꢀ
ing Information for details). As the results have previously
been communicated,35 only the major findings are briefly
summarized herein.
Scheme 3. Free Energy Profile for the trans-Hydrogenation
of 2-Butyne with Complex [Cp*Ru(cod)Cl]
According to DFT, the reaction commences by formation
of a ruthenium complex A1 loaded with 2ꢀbutyne as the model
substrate and H2 (Scheme 3). In A1, H2 is bound via its σꢀ
bond;55,56 this computational result nicely accords with early
experimental observations which had shown that the structurꢀ
57
ally wellꢀdefined σꢀcomplex [Cp*Ru(H−H)(cod)]OTf
is a
competent transꢀhydrogenation catalyst.30 A1 converts into
metallacyclopropene (η2ꢀvinyl complex) E1;58 this key interꢀ
mediate evolves via the fairly lowꢀlying stereochemistryꢀ
determining transition state TSE1-E2 (ꢀꢀG≠ = 5.1 kcal⋅molꢀ1,
relative to E1) into the desired Eꢀ2ꢀbutene (E2). The productꢀ
forming step is exergonic by 33.6 kcal⋅mol−1 and therefore
almost certainly irreversible. The computed pathway to the Zꢀ
alkene, though viable, has a barrier that is higher by 3.4
kcal⋅mol−1 (not shown in Scheme 3),35 which concords with
the generally excellent experimental E/Zꢀratios.
A particularly striking computational result with important
ramifications is the observation that the reaction pathway
bifurcates at the stage of the ruthenacyclopropene E1 (Scheme
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Journal of the American Chemical Society
(Scheme 5), H2 has first to be coordinated but will get released
4): this intermediate cannot only convert into the desired Eꢀ
1
2
3
4
5
6
7
8
alkene E2 by a concerted mechanism, but can also evolve into
a ruthenium carbene C2 via a transition state that is computed
at the chosen level of theory to be only 1.2 kcal⋅mol−1 higher in
energy. Because carbene formation is not only facile but also
strongly exergonic, it is reasonable that intermediates of this
type are observable by PHIP NMR or even stable enough for
isolation in favorable cases. Moreover, the DFT results ascerꢀ
tain that both Hꢀatoms of the newly formed methylene group
in C2 derive from the same H2 molecule (“gemꢀ
hydrogenation”), which is mandatory for the PHIP effect to be
operative.36,37 Hence the overall computational scenario is in
excellent agreement with the experimental data.
again en route to the desired product E2 and the isomerized
alkene D4; H2 hence serves as a “catalyst” in that it features as
a reagent and as a product alike. Under this premise, the
EXSY spectra should also have a cross peak between carbene
7b and the “product” H2; Figure 6 shows that this is indeed the
case.
To further strengthen the argument, we subjected the deuꢀ
terated substrate [D3]ꢀ4b to the same reaction conditions.
Formation of the isomeric alkene [D2]ꢀ16 by the proposed
associative mechanism mandates association of H−H but
release of H−D (Figure 10). This product was unambiguously
identified in the 1H NMR spectra by virtue of its characteristic
coupling pattern. Alternative sources of H−D, e. g. via C−D
bond activation, are deemed improbable, since such behavior
is currently unknown for the chosen catalyst. Hence, the availꢀ
able NMR data nicely validate the computed scenario in all
regards: they do not only confirm the overall product spectrum
but also speak for an associative character of the steps downꢀ
stream of C2.
9
10
11
12
13
14
15
16
17
18
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21
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51
52
53
54
55
56
57
58
59
60
The fate of carbene C2 turns out to be largely selectivity deꢀ
termining (Scheme 5). The unimolecular reverse reaction to
E1 is high in energy; yet, C2 is a 16e species that can bind an
extra ligand, which might lower the barriers. In fact, DFT
suggests that coordination of a second molecule of H2 opens a
favorable outlet. Details apart, this associative mechanism
leads to the desired product Eꢀ2ꢀbutene, the isomeric product
1ꢀbutene (D4) and fully saturated butane (B2).35 All of these
reaction channels have fairly low barriers of similar magniꢀ
tude; the actual product spectrum depends on steric parameters
which determine the side from which H2 approaches the
[Cp*Ru=C] unit.35
DFT Study Using a Functionalized Substrate. Since an
associative mechanism largely determines the fate of a 16eꢀ
carbene species of type C2, it is obvious why its 18e anaꢀ
logues 6e, 7d, 9b and 12 are kinetically rather stable even
under H2 atmosphere. As long as the necessary coordination
site at ruthenium is blocked by the –OR substituent, uptake of
H2 is prevented and hence the computed lowꢀenergy pathways
are basically shut off.
Experimental Scrutiny. The conclusions drawn from the
DFTꢀstudies are in excellent accord with the available experiꢀ
1
mental results. The fact that the 2D HꢀOPSYꢀEXSY experiꢀ
ment linked the carbene 7b to product 5b, the positional isoꢀ
mer 16 and the fully saturated product 17 (Figure 6) correꢀ
sponds perfectly to the computed scenario; yet, congruence
between predicted and observed product distribution does not
prove that the pathway is associative in nature as suggested by
DFT.
To put intuition on a firmer basis, the reaction of substrate
8b with [Cp*Ru(cod)Cl] and H2 was computed at the same
level of theory (Scheme 6). As expected, the propargylic subꢀ
stituents alter the free energy landscape to a significant extent:
Specifically, the barrier to ruthenacyclopropene formation (A1
→ E1) is lowered by no less than 8 kcal⋅mol−1, largely due to
hydrogen bonding between the −OH group and the [Ru−Cl]
unit. Moreover, conversion of E1 into carbene C2 is now
preferred over concerted Eꢀalkene formation by 2.6
kcal⋅mol−1. Again, the stabilizing effect of the lateral substituꢀ
ents is significant as decomplexation of the –OMe group from
the ruthenium center of C2 with formation of C2’ entails a 6.5
kcal⋅mol−1 enthalpic penalty. Suffice it to say that the computꢀ
ed structural features of C2 nicely reproduce the crystal strucꢀ
ture of this complex (9b)35 and hence lend further credence to
the computed scenario.
HD
These results showcase that functional groups in the vicinity
of the triple bond exert a massive influence on the reaction
coordinate. For 8b as the substrate, the ruthenium carbene 9b
(= C2) actually represents a thermodynamic sink, which exꢀ
plains why we managed to isolate this species. While the
appreciable influence of the chemical microenvironment on
the stability of the reaction intermediates evident from this
example has implications for the scope of transꢀhydrogenation
in general, it also opens new vistas for harnessing genuine
carbene chemistry. Exploratory studies along these lines are
outlined below.
o-H2
δ
(1H) / ppm
Figure 10. Formation of H−D during the hydrogenation of
[D3]ꢀ4b is indicative of an associative mechanism downstream
the carbene intermediate [D3]ꢀ7b
Under the proviso that the calculations capture the essence
of the transformations downstream of carbene C2 correctly
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Scheme 6. Computed Pathway of the Reduction of the Functionalized Alkyne 8b (free energies relative to 8b, kcal⋅mol−1)
1
2
3
4
5
6
7
8
Cp*
Cp*
Cl
Cl
H
O
1,2-H shift
Ru
H
H
O
Ru
H
H
E-alkene
alkane
H
O
CH3
O
CH3
H
*Cp
Cl
H
*Cp
Cl
Cp*
Ru
H
H
H
H
Cl
H
TSE1-E2 (17.7)
TSR1'-R3' (29.6)
Ru
H
O
Ru
H
O
H
O
H
8b
CH3
O
O
CH3
O
CH3
+H2
9
A1 (12.2)
TSA2-A3 (19.9)
E1 (9.4)
10
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46
47
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49
50
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53
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55
56
57
58
59
60
Cp*
Ru
Cp*
Cp*
Cl
Cl
Cl
CH3
O
Ru
H
Ru
H
H
O
H
O
H
O
O
CH3
O
CH3
H
H
H
H
C2 (-8.8)
TSE1-C2 (15.1)
C2' (-2.3)
Scheme 7. Overlay of the DFT and CCSD(T) Free Energy Profiles for the Reactions Yielding the E-Alkene (E2) and the
Carbene Complex C2
CCSD(T) differ by less than 2 kcal⋅molꢀ1. Compared with
DFT, CCSD(T) gives notably higher energies for the loaded
complex A1 and for the products E2 and C2 (higher by up to 5
kcal⋅molꢀ1). More significant from a mechanistic point of view
is that CCSD(T) eliminates the slight kinetic preference for
direct Eꢀalkene formation (E1 → E2) over carbene generation
(E1 → C2) that DFT had predicted, with the difference in the
relevant transition state energies changing from ꢀ2.0 to +0.5
kcal⋅molꢀ1 (Scheme 7). At the same time, CCSD(T) lowers the
barrier for reversion of carbene C2 to E1 while increasing the
relative energies of all intermediates downstream to C2 by
typically 2ꢀ3 kcal⋅molꢀ1 (see Figures S2 and S3 in the Supportꢀ
ing Information). For the H2 associative pathways that lead to
the side products by olefin isomerization or overꢀreduction,
the DFT and CCSD(T) results are again qualitatively similar,
with only minor deviations in the computed relative free enerꢀ
gies (see Supporting Information).
Coupled Cluster Study Using 2-Butyne as the Model
Substrate. The DFTꢀcomputed barriers for the pathways
leading from the key metallacyclopropene E1 to the Eꢀalkene
E2 and the ruthenium carbene C2 are small but selectivityꢀ
determining. Generally speaking, DFT energy differences of a
few kcal⋅molꢀ1 have to be met with caution. We therefore
decided to perform more accurate singleꢀpoint coupled cluster
calculations at the DFTꢀoptimized geometries, in order to
achieve chemical accuracy (1 kcal⋅molꢀ1) for the computed
relative energies. More specifically, we employed the domainꢀ
based pair natural orbital coupled cluster method with single
and double excitations, DLPNOꢀCCSD, and with a perturbaꢀ
tional estimate of the triples contributions, DLPNOꢀ
CCSD(T).59 The computational details and the numerical
results are fully documented in the Supporting Information.
The CCSD and CCSD(T) results are generally close to each
other (see Supporting Information). Hence we focus here on
the comparison between the DFT and our most accurate
CCSD(T) free energy profiles for the pathways leading from
the reactants to E2 and C2 (Scheme 7).
In summary, it is gratifying that the gross mechanistic picꢀ
ture remains unchanged when going from the DFT to the more
accurate CCSD(T) level. However, the overlay shown in
Scheme 7 also indicates that the selectivityꢀdetermining facꢀ
tors are very subtle and that great care is needed when trying
to predict product distributions computationally. In the present
case, the more accurate coupled cluster calculations suggest
Overall, the two profiles shown in Figure 7 are qualitatively
similar, and in most cases the relative energies from DFT and
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ty as reached with 1,2ꢀdichloroethane (instead of CH2Cl2) as
that the carbene C2 is even more easily accessible than anticiꢀ
1
2
3
4
5
6
7
8
pated from the DFT calculations. This reinforces the concluꢀ
sion that it is a key intermediate which plays an important
mechanistic role.
the solvent. In general, tertꢀpropargyl alcohols gave the best
results. Although the selectivity for transꢀreduction was equalꢀ
ly high for their secꢀ and primary congeners, redox isomerizaꢀ
tion with formation of enones is a competing process lowering
the yields; this reaction is induced by the same type of rutheꢀ
nium catalysts.60,61 Since amides, sulfonamides and carbaꢀ
mates exert a similar steering effect as –OH groups,24 it is
unsurprising that formation of compound 29 was also effecꢀ
tive.
Preparative Implications: trans-Hydrogenation of Func-
tionalized Propargylic Alcohols. The spectroscopic, crystalꢀ
lographic and computational study outlined above suggested
that propargyl alcohol derivatives might be good candidates
for transꢀhydrogenation: the –OH group should block the
coordination site necessary for secondary H2 binding and
hence increase the chance that the carbene reverts to the metalꢀ
lacyclopropene and evolves from there on to the desired Eꢀ
alkene. In any case, this class of compounds had previously
not been studied. Although amenable to LiAlH4 (or RedꢀAl)
reduction, this standard method cannot be applied whenever
the substrate bears additional reducible functionality.
9
The transꢀhydrogenation proved compatible with many (reꢀ
ducible) functional groups, including aldehyde, ketone, acetal,
ether, ester, enoate, alkene, nitrile, sulfonamide and aryl broꢀ
mide; even a nitro substituent passed uncompromised. A parꢀ
ticularly striking feature is the ability to distinguish between
the propargylic triple bond and a silylated alkyne unit, which
remained unchanged (31); such chemoselectivity is difficult to
accomplish in ordinary hydrogenation reactions. Albeit not
reducible itself, an aniline derivative could act as a potential
ligand to ruthenium, yet did not interfere with the reaction
(25). Reactivity was basically lost when the –OH group was
blocked in form of a methyl ether (37) as this change likely
renders the carbene intermediate too stable (compare comꢀ
plexes 7d, 12a). Other limitations were encountered with the
primary homoꢀpropargyl alcohol 36 or in cases in which the
catalyst might get trapped by a competing binding site or via
chelation, as is the case when the nitrile or an ordinary alkene
is placed ortho to the triple bond (38, 39).
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49
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52
53
54
55
56
57
58
59
60
Scheme 8. trans-Hydrogenation of Propargyl Alcohol De-
rivatives and Related Substratesa
Applications. The 3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀbutenyl group is a
biogenetic modification of the prenyl residue present in innuꢀ
merous natural products. Although this moiety can a priori be
introduced in one step by a Heck reaction, previous applicaꢀ
tions of this venerable transformation to murraol (41),62
a
secondary metabolite originally isolated from leaves of Mur-
raya exotica (Rutaceae), gave very modest results as reported
by two different laboratories (28ꢀ40%).63 We were therefore
pleased to learn that a sequence of Sonogashira coupling folꢀ
lowed by transꢀhydrogenation was clearly more effective
(Scheme 9). The isomeric product Eꢀsuberenol (43) was equalꢀ
ly well accessible in good overall yield. This particular coumaꢀ
rin derivative was isolated from different plants and is found
as an ingredient in various beverages.64
The excellent chemoselectivity of the reaction opened an
efficient approach to compound 47, which is an odoriferous
constituent of sunꢀcured tobacco (Scheme 10).65 Allylic oxidaꢀ
tion of the acetal derived from 44 followed by bromination of
the resulting alcohol furnished product 45 in readiness for
copperꢀmediated coupling with the dianion derived from 2ꢀ
methylꢀ3ꢀbutynꢀ2ꢀol. Provided the reaction was carried out at
−30°C, competing SN2’substitution was largely suppressed.
Acetal cleavage furnished enyne 46, which underwent clean
transꢀhydrogenation at 70°C. As expected on the basis of the
model studies outlined above, only the triple bond got reduced
to give the target compound 47, whereas neither the alkene nor
the ketone function was affected under the chosen conditions.
a
Unless stated otherwise, the reactions were carried out in
CH2Cl2 at RT; b in 1,2ꢀdichloroethane at 70°C
With the hope to fill this methodological gap, we investigatꢀ
ed the transꢀhydrogenation of a representative set of propargyl
alcohol derivatives (Scheme 8). Although aromatic rings can
block the active [Cp*Ru] catalyst by η6ꢀcoordination,31 this
deleterious effect is offset by the assistance that the hydroxy
group does provide in binding of the metal fragment to the
triple bond.27 In line with this notion, tertꢀpropargyl alcohol
derivatives with aryl substituents were found to react smoothly
in the presence of [Cp*RuCl]4 (1ꢀ2 mol%) in CH2Cl2; in most
cases, the transꢀhydrogenation proceeded at ambient temperaꢀ
ture at only 1 bar H2 pressure. Substrates with aliphatic rather
than aromatic substituents on the triple bond reacted similarly
well but tend to require higher temperatures for good selectiviꢀ
Scheme 11 shows the formation of product 53 correspondꢀ
ing to the head piece of fostriecin, which had served as a
prominent target in the past.66 Addition of 50 to freshly preꢀ
pared aldehyde 49 followed by acylation of the resulting secꢀ
ondary alcohol with acryloyl chloride set the stage for the
closure of the δꢀlactone ring by RCM and subsequent removal
of the TESꢀether with buffered TBAF.67 The quite acid sensiꢀ
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tive product 52 was then transꢀhydrogenated to give 53 as a
complexes, which has been studied in the past not nearly as
extensively as that of other ruthenium carbene species.69
1
2
3
4
5
6
7
fostriecin model, without touching the equally reducible enoꢀ
ate entity. To properly assess this outcome, we refer to a reꢀ
cent literature report that described the failure of all attempts
to semiꢀreduce the triple bond of the very closely related subꢀ
strate 54 unless the lactone was first treated with DibalꢀH and
the resulting hemiketal converted into the corresponding isoꢀ
propyl glycoside.68
Scheme 11. Application of trans-Hydrogenation to a Fos-
triecin Model Compound.a
8
9
Scheme 9. Preparation of Murraol (41) and E-Suberenol
(43).a
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58
59
60
a
a
Reagents and conditions: a) I2, KI, aq. NH3; b) MeI, K2CO3,
Reagents and Conditions: a) NaIO4, CH2Cl2, H2O; b) 49,
acetone, 24% (over both steps); c) 2ꢀmethylꢀbutꢀ3ꢀynꢀ2ꢀol,
[(Ph3P)2PdCl2] cat., CuI, PPh3, Et3N, DMF, 88%; d) H2 (1
bar), [Cp*RuCl]4 (2 mol%), CH2Cl2, 81% (Eꢀalkene/alkane =
89:11); e) NaOMe. MeOH, 65°C; f) I2, KI, aq. NH3, then
Ph2O, 190°C, 24% (overall); g) 2ꢀmethylꢀbutꢀ3ꢀynꢀ2ꢀol,
[(Ph3P)2PdCl2] cat., CuI, PPh3, Et3N, DMF, 81%; h) H2 (1
bar), [Cp*RuCl]4 (2 mol%), CH2Cl2, 84%
nBuLi, THF, 55% (over both steps); c) acryloyl chloride,
iPr2NEt, CH2Cl2, 91%; d) HGII (3 x 2 mol%), 1,2ꢀ
dichloroethane, 70°C, 48%; e) TBAF, HOAc, THF, 62%; f)
H2 (1bar), [Cp*RuCl]4 (2 mol%), 1,2ꢀdichloroethane, 40°C,
61%
In a first foray, enyne 55 was hydrogenated under standard
conditions. We were pleased to find that the cyclopropyl deꢀ
rivative 56 was formed in excellent yield, evidently via forꢀ
mation and interception of a ruthenium carbene analogous to
the complexes of type 7 outlined above. Ynoate 57 also reactꢀ
ed well to give the cyclopropyl ketone 58 as the major prodꢀ
uct. From the conceptual viewpoint, this example is significant
as it shows that ynones can serve as stable surrogates for αꢀ
diazo ketones which had found numerous applications in synꢀ
thesis the past.70ꢀ72 This equivalence forecasts ample opporꢀ
tunity for further studies in this field.73,74
Scheme 10. Preparation of an Odoriferous Tobacco Con-
stiutent.a
a
Reagents and conditions: a) ethylene glycol, pꢀTsOH cat.,
The case of the Nꢀtethered enyne 59 is also noteworthy: on
treatment with [Cp*RuI]4 at 70°C, appreciable amounts of
cyclopropane 60 were formed (in addition to 9% of the exꢀ
pected transꢀhydrogenation product). Importantly, the use of
complex 6275 changed the regiochemical course of cyclization
in that it led to cyclopropane 61 as the major product. We
tentatively ascribe this catalyst control over the pathway of
hydrogenative cyclopropanation to the more bulky and more
electron rich cyclopentadienyl ligand in 62 which favors carꢀ
bene formation distal to the equally bulky tertiary alcohol site
on steric grounds.
benzene, 80°C, 55%; b) SeO2, tBuOOH, CH2Cl2, 0°C, 51%; c)
NBS, PPh3, CH2Cl2, −30°C, 74%; d) 2ꢀmethylꢀ3ꢀbutyneꢀ2ꢀol,
nBuLi, CuI, THF, −30°C, 69%; e) pꢀTsOH cat., acetone, H2O,
62%; f) H2 (1 bar), [Cp*RuCl]4 (2 mol%), 1,2ꢀdichloroethane,
70°C, 60%
Harnessing Genuine Carbene Reactivity. Our experiꢀ
mental and computational data show that properly placed
substituents in vicinity to the triple bond to be hydrogenated
instigate formation of metastable ruthenium carbenes in the
first place; it requires binding and activation of a second H2
molecule for such intermediates to reꢀenter the catalytic cycle
resulting in hydrogenation. We conjectured that it might be
possible to outperform this step − even under an H2 atmosꢀ
phere − by kinetically favorably (intramolecular) processes
and, in doing so, harness prototypical metal carbene chemisꢀ
try. To this end, however, it is necessary to explore the innate
reactivity of pianoꢀstool cyclopentadienyl ruthenium carbene
Even though it is certainly much more challenging to outꢀ
perform hydrogenation by C−Cꢀbond formation in intermolecꢀ
ular settings, the fully characterized carbene 12a reacted with
ethylene (1 bar). Cyclopropane 64 was only the minor product
(12%, NMR), but the formation of alkenes 65 (60%, NMR)
and 66 (28%, NMR) suggests the intervention of a metallacyꢀ
clobutane of type 63. Although this aspect needs further scruꢀ
tiny, the outcome is reminiscent of certain enyne metathesis
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excellent yield. Just like the hydrogenative cyclopropanation,
reactions with ethylene as partner, which afforded cycloproꢀ
1
2
panes as byꢀproducts when [Cp*Ru]ꢀbased catalysts were
these hydrogenative ring expansion reactions seem to be the
first of their kind.
employed.76
3
4
5
6
Scheme 12. Hydrogenative Cyclopropanation
Scheme 13. Hydrogenative 1,2-Alkyl Shift Reactions and
Attempted C-H Insertion
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59
60
Scheme 14. Hydrogenative [3+2] Cycloaddition
Finally, hydrogenative carbene formation followed by a
formal [3+2] cycloaddition was accomplished using acetylene
dicarboxylate 75. For symmetry reasons, a single carbene
isomer can emerge from this substrate, which condenses with
unreacted 75 to give the furan derivative 76; in contrast to the
previous examples, THF rather than CH2Cl2 was the solvent of
choice, as it largely suppressed competing [2+2+2] cyclotriꢀ
merization of the substrate.
Formation of a cyclopropane via metalꢀcatalyzed hydroꢀ
genation of an enyne is a highly unorthodox and perhaps even
counterintuitive transformation; to the best of our knowledge,
it is without precedent in the literature. While an attempt at
extending this reactivity pattern to CHꢀinsertion into an acetal
has so far been unsuccessful but mainly led to overꢀreduction
of substrate 67 with formation of product 68, prototypical
carbene reactivity could be harnessed in form of 1,2ꢀalkyl shift
reactions.77,78 Specifically, substrates 70 and 73 were chosen
as they are expected to lead to the formation of a single carꢀ
bene isomer such as 71, residing proximal to the –OH and
distal to the −OMe substituent. We conjectured that a strainꢀ
driven ring expansion might compete with activation of a
second H2 molecule and hence outperform transꢀreduction
and/or overꢀreduction of the substrate. The peripheral
−OH⋅⋅⋅⋅Cl hydrogen bonding array could provide further assisꢀ
tance, as it facilitates the necessary proton transfer during or
after the rearrangement. In fact, the reactions were very clean,
affording the corresponding ketones 72 and 74 in essentially
quantitative assay yields; the volatility of 72, however, led to
some loss during isolation, whereas 74 was indeed obtained in
CONCLUSION
A combined experimental and computational approach alꢀ
lowed a concise scenario of rutheniumꢀcatalyzed alkyne transꢀ
hydrogenation to be drawn. The reaction differs from basically
all other known procedures for the reduction of triple bonds to
Eꢀalkenes in that it does not involve formation of a Zꢀalkene in
the first place followed by isomerization to the thermodynamiꢀ
cally more stable Eꢀisomer; rather, the two Hꢀatoms are truly
delivered in a transꢀfashion via a metallacyclopropene (η2ꢀ
vinyl complex) as the key intermediate. It is shown that proꢀ
pargyl alcohols are excellent substrates that have not been
investigated before; many reducible functional groups proved
compatible with catalytic transꢀhydrogenation that would not
subsist under more conventional conditions.
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(6) For other functional groupꢀtolerant Zꢀselective semiꢀ
Olefin isomerization and overꢀreduction are the most seriꢀ
ous side reactions that compete with transꢀhydrogenation.
These transformations largely derive from pianoꢀstool Cp*Ruꢀ
carbene species, the formation of which competes with the
productive evolution of the ruthenacyclopropene to the Eꢀ
alkene. From the conceptual viewpoint, however, this hydroꢀ
genative entry into metal carbenes is remarkable as it manꢀ
dates delivery of both Hꢀatoms of H2 to the same Cꢀatom of
the substrate; such geminal hydrogenations of ordinary organꢀ
ic compounds are largely unprecedented. This novel entry into
carbenes opens new opportunities for reaction development as
illustrated by unorthodox hydrogenative cyclopropanation,
hydrogenative ring expansion and hydrogenative [3+2] cyꢀ
cloaddition reactions. These transformations deserve further
study in their own right and insinuate that yet other creative
ways of harnessing genuine carbene reactivity via hydrogenaꢀ
tion of unsaturated substrates might await discovery.
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F. Synthesis 2017, 49, 2470.
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ASSOCIATED CONTENT
Supporting Information. Experimental part including characterꢀ
ization data, NMR spectra of new compounds, and supporting
crystallographic information.
(8) Diimide often leads to overꢀreduction, see: (a) Buszek, K. R.;
Brown, N. J. Org. Chem. 2007, 72, 3125. (b) Menges, N.; Balci, M.
Synlett 2014, 25, 671. (c) Good selectivity, however, is achieved with
certain functionalized substrates such as haloalkynes; for a representaꢀ
tive example, see: Denmark, S. E.; Yang, S.ꢀM. J. Am. Chem. Soc.
2004, 126, 12432.
Computational part including methodological details, energy
tables and additional energy profiles
Xꢀray crystallographic data (CIF)
(9) (a) Pasto, D. J. In Comprehensive Organic Synthesis: Selectivi-
ty, Strategy & Efficiency in Modern Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8; pp 471ꢀ488.
(b) Dieter, R. K. Sci. Syntt. 2006, 8, 43. (c) Kaiser, E. M. Synthesis
1972, 391. (d) Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J. W.;
Mäeorg, U. Eur. J. Org. Chem. 1999, 775. (e) Kovářová, I.; Streinz,
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4358. (b) Smith, A. B.; Levenberg, P. A.; Suits, J. Z. Synthesis 1986,
184. (c) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117,
8106.
(11) Homopropargyl alcohols and ωꢀalkynols: (a) Rossi, R.; Carpiꢀ
ta, A. Synthesis 1977, 561. Thioalkynes: (b) Hojo, M.; Masuda, R.;
Takagi, S. Synthesis 1978, 284. Chloroalkynes: (c) Zweifel, G.; Lewꢀ
is, W.; On, H. P. J. Am. Chem. Soc. 1979, 101, 5101. Alkynylamines:
(d) Eisch, J. J.; Gopal, H.; Rhee, S.ꢀG. J. Org. Chem. 1975, 40, 2064.
Alkynylsilanes (stannanes, germanes, phosphines): (e) Eisch, J. J.;
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AUTHOR INFORMATION
Corresponding Author
* fuerstner@kofo.mpg.de
Present Addresses
† L. M. W.: Department of Chemistry, University of Massachuꢀ
setts Lowell, 1 University Avenue, Lowell, MA 01854, USA
ACKNOWLEDGMENTS
Generous financial support by the MPG is gratefully acknowlꢀ
edged. We thank K. Radkowski, Dr. B. Sundararaju and Dr. M.
Fuchs, for the initial work on transꢀhydrogenation and the analytꢀ
ical departments of our Institute for excellent support.
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