Ruthenium dihydride complexes as enyne metathesis catalysts

Article abstract of DOI:10.1016/j.tetlet.2018.11.016

Ruthenium–catalyzed enyne metathesis is a reliable and efficient method for the formation of 1,3-dienes, a common structural motif in synthetic organic chemistry. The development of new transition-metal complexes competent to catalyze enyne metathesis rea

Full text of DOI:10.1016/j.tetlet.2018.11.016

Accepted Manuscript
Ruthenium Dihydride Complexes as Enyne Metathesis Catalysts
Martin A. Dolan, Alexandre D.C. Dixon, John D. Chisholm, Daniel A. Clark
PII:
S0040-4039(18)31332-7
https://doi.org/10.1016/j.tetlet.2018.11.016
TETL 50401
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
20 September 2018
2 November 2018
5 November 2018
Please cite this article as: Dolan, M.A., Dixon, A.D.C., Chisholm, J.D., Clark, D.A., Ruthenium Dihydride
Complexes as Enyne Metathesis Catalysts, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.11.016
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Ruthenium Dihydride Complexes as Enyne
Metathesis Catalysts
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Martin A. Dolan, Alexandre D. C. Dixon, John D. Chisholm* and Daniel A. Clark*

1
Tetrahedron Letters
Ruthenium Dihydride Complexes as Enyne Metathesis Catalysts.
Martin A. Dolan, Alexandre D. C. Dixon, John D. Chisholm and Daniel A. Clark*
aDepartment of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ruthenium–catalyzed enyne metathesis is a reliable and efficient method for the formation of
1,3-dienes, a common structural motif in synthetic organic chemistry. The development of new
transition-metal complexes competent to catalyze enyne metathesis reactions remains an
important research area. This report describes the use of ruthenium (IV) dihydride complexes
with the general structure RuH2Cl2(PR3)2 as new catalysts for enyne metathesis. These
ruthenium (IV) dihydrides have been largely unexplored as catalysts in metathesis-based
transformations. The reactivity of these complexes with 1,6 and 1,7-enynes was investigated.
The observed reaction products are consistent with the metathesis activity occurring through a
ruthenium vinylidene intermediate.
Available online
Keywords:
Metathesis
Enyne
2018 Elsevier Ltd. All rights reserved.
Alkyne
1,3-Diene
Ruthenium
Dihydride
The synthesis of substituted 1,3-dienes remains an active
research area, as these motifs are commonly encountered in
natural products1 and have applications in materials science.2 A
number of palladium-catalyzed cross coupling approaches to 1,3-
dienes have been developed to facilitate the synthesis of these
systems.3 In most of these cases the formation of the 1,3-diene is
accomplished by the coupling of vinyl halides and vinyl metal
intermediates. Installation of a diene with these methods is
accompanied by significant waste generation, with loss of
stoichiometric amounts of both a halogen (or pseudohalogen) and
metal (or metalloid) being responsible for the poor atom
economy.4 Many of the precursors for the vinyl starting materials
are generated from alkyne precursors, so it is unsurprising that
methods are continuously being developed to circumvent the
need for the formation of the vinyl halide or vinyl metal
intermediates; they instead focus on proceeding directly from an
alkyne to a 1,3-diene product.5
Enyne metathesis,6 where a ruthenium carbene complex
catalyzes an addition reaction between an alkene and an alkyne,
is one example of the direct formation of a 1,3-diene from
unactivated precursors (Scheme 1). Unlike palladium catalyzed
cross couplings, enyne metathesis both creates a new carbon-
carbon bond and provides a new arrangement of unsaturated
functionality, arriving at the conjugated 1,3-diene with complete
atom-economy. Intermolecular enyne metathesis may be
performed with nearly equal amounts of alkyne and alkene to
provide the 1,3-diene product, demonstrating high efficiency of
the process.7 Enyne metathesis may be performed in an
intramolecular or intermolecular fashion, providing both cyclic
and acyclic products respectively. Typically ruthenium
alkylidene catalysts like the ones developed by Grubbs (3 and
4)8,9 or Hoveyda (5)10 are used to execute these transformations.
Scheme 1. Overview of enyne metathesis transformation and
commonly used catalysts
The development of new transition metal complexes
competent to catalyze enyne metathesis reactions with high
turnover, useful regio- and stereocontrol, and which allow access
to diverse substitution patterns on the diene product is still an
active research area. As an extension of our work on ruthenium
hydrides,11 the reactivity of the ruthenium dihydride 7 with 1,7-
enyne 6 was evaluated (Scheme 2). Our intent was to provide a
new route to the exocyclic 1,3-diene 9, however careful
1
consideration of the H and 13C NMR of the reaction product
indicated clean conversion to the endocyclic diene 8 in moderate
yield. Diene 8 is more commonly accessed from traditional ring
closing enyne metathesis (RCEYM). To further verify formation
of the RCEYM product, the use of Grubbs-I catalyst under
Mori’s conditions (3 mol % Grubbs-I, 0.01 M DCM, 1 atm
ethylene)12 was performed and provided 8 which was identical in
all respects to the product obtained in Scheme 2. Ruthenium
dihydrides have been utilized as catalysts in carbon-carbon bond

2
forming reactions previously13 and this subject has been
reviewed.14
10, the reaction parameters were re-examined. Performing the
transformation in toluene at room temperature (0.05 M) gave
diene 8 in 73% yield (entry 8). Interestingly, dichloromethane
under similar conditions with complex 10 also gave a good yield
of 8 (entry 9). This concentration was utilized throughout later
experiments, as further dilution to 0.025 M did not show
improvement. Decreasing the amount of complex 10 led to
increased yield of 8 (entries 11-13), with 3 mol % loading being
optimal. Evaluation of the previously unreported ruthenium
dihydride RuH2Cl2(P(t-Bu2)Cy)2 11 under similar reaction
conditions showed no metathesis activity, presumably due to the
increased steric bulk of the di-tert-butylcyclohexylphosphine
(entry 15).
The mechanism of the enyne metathesis with these dihydride
catalysts was also considered (Scheme 3). Previously, ruthenium
dihydrides have been utilized as intermediates in the formation of
other ruthenium complexes,15 including vinylidene type
complexes analogous to 13 which formed upon addition of
terminal alkynes or propargylic alcohols.16 These vinylidenes
strongly resemble proposed intermediates within the commonly
invoked enyne metathesis catalytic cycle.17 Entry into an enyne
metathesis catalytic cycle commences with [2+2] cycloaddition
of ruthenium vinylidene 13 and alkyne 12. Previous NMR studies
in the literature support the hypothesis that the enyne metathesis
with ruthenium catalysts usually occurs via the ene-then-yne
pathway.18 A retro [2+2] (as shown in 15) then provides
formation of the vinyl ruthenium carbene species 17 which is the
key intermediate for enyne metathesis.6a,6c,6e Vinyl ruthenium 17
then proceeds to ruthenacyclobutene 18, which upon
cycloreversion gives the alternate complex 19. Cycloaddition of
19 with enyne 12 then leads to ruthenacyclobutane 20, which
upon cycloreversion extrudes the diene product 21 and
regenerates the key intermediate alkylidene 17, allowing for
catalyst turnover.
Scheme 2. Enyne metathesis by ruthenium dihydride 7
We set out to optimize the reaction conditions to determine if
comparable yields could be obtained compared to the more
common ruthenium alkylidenes (3-5, Scheme 1). Initially a
solvent screen was conducted (Table 1). Chlorinated solvents
were first examined, as these were used to good effect by
Mascarenas and co-workers in their intramolecular
cycloadditions of allenes utilizing dihydride 7.13c Reaction in
DCM at room temperature provided RCEYM product 8 in 19%
yield after 24 hours (entry 1). Increasing the temperature and
switching to 1,2-dichloroethane (DCE) gave a similar yield of
20% in a shorter reaction time (5 hours) (entry 3). Other solvents
were also examined, with toluene proving to be the most
effective with catalyst 7 (entry 5). The effect of concentration
was then explored, with a small improvement in yield (42%)
being observed upon dilution to 0.10 M (entry 6). Other
ruthenium complexes were examined to improve the
transformation, with RuH2Cl2(P(t-Bu)2Me)2 (10) providing a
68% yield (entry 7). Given the better performance from complex
Table 1. Optimization of Reaction Conditionsa
Entry Catalyst
Catalyst Loading Solvent Temperature (°C) Concentration [M] Time (h) Yieldb
1
RuH2Cl2(P(i-Pr)3)2 (7)
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
DCM
THF
rt
0.25
0.25
0.25
0.25
0.25
0.10
0.10
0.05
0.05
0.025
0.05
0.05
0.05
0.05
0.05
24
24
5
19
27
20
32
38
42
68
73
66
73
76
82
84 (72)
18
0
2
RuH2Cl2(P(i-Pr)3)2 (7)
RuH2Cl2(P(i-Pr)3)2 (7)
RuH2Cl2(P(i-Pr)3)2 (7)
RuH2Cl2(P(i-Pr)3)2 (7)
RuH2Cl2(P(i-Pr)3)2 (7)
66
86
110
3
DCE
4
CPME
2
5
toluene 110
toluene 110
toluene 110
toluene rt
1.5
4.5
5
6
7
RuH2Cl2(P(t-Bu)2Me)2 (10) 10 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 10 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 10 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 10 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 5 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 5 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 3 mol %
RuH2Cl2(P(t-Bu)2Me)2 (10) 1 mol %
RuH2Cl2(P(t-Bu)2Cy)2 (11) 5 mol %
8
1.5
0.5
1.5
1
9
DCM
rt
10
11
12
13
14
15
toluene rt
toluene rt
DCM
DCM
DCM
DCM
rt
rt
rt
rt
2.5
3.5
24
1
aTrials performed on a 0.20 mmol scale under Ar atmosphere.
bYields were determined from 1H NMR using mesitylene as an internal standard, isolated yields are reported in parentheses.

3
33 and spirocyclic diene 35 also participated in the RCEYM,
providing yields of 42% and 40% respectively. While the method
was widely applicable to propargyl and homopropargyl terminal
alkynes, metathesis was not observed with an internal alkyne
(entry 6, substrate 36). RCEYM of sulfonamides was also
demonstrated, accessing dihydropyrrole 39 in 78% yield.
Piperidine 41 was also furnished in excellent yield, accessed
from one of two sulfonamides, 40 or 42. Metathesis was also
demonstrably effective with the malonate substituted enyne 43,
resulting in the synthesis of cyclopentene 44.
Table 2. Scope of the New Enyne Metathesis Catalyst
Entry
1b
Enyne
1,3-Diene
Yielda
84
(72)
61
(58)
2
3c
4
Scheme 3. Proposed mechanism for ruthenium dihydride
catalyzed enyne metathesis
85
(72)
Efforts were also made to provide experimental evidence to
support this mechanistic proposal. First, deuterated alkyne 22
was employed to verify the fate of the alkynyl hydrogen
(equation 1). Exposing enyne 22 to the reaction conditions gave
the expected deuterated 1,3-diene 23 in 86% yield as determined
42
40
1
by H NMR (56% isolated yield). This material retained the
deuterium label (~97% D) originally included from the enyne,
supporting the mechanism shown in Scheme 3. Additionally, the
formation of the vinylidene intermediate from an alkyne was
explored with the use of alkyne additives. Using diallyl
dimethylmalonate 24, two reactions were conducted with and
without the use of the alkyne additive phenylacetylene (equations
2 and 3). With no added phenylacetylene, ring closing metathesis
was not observed. Addition of (5 mol %) phenylacetylene to the
dihydride complex 10 afforded cyclopentene 25 in 77% yield.
This further suggests the formation of a metathesis active
vinylidene species.
5
6
0
88
(78)
7
8
83
(56)
78
9d
10
62
aYields were determined from 1H NMR using mesitylene as an internal
standard, isolated yields are reported in parentheses.
c Reaction was complete in 6.5 h.
b3 Mol % of the catalyst was used and the reaction was complete in 3.5 h.
d7.5 Mol % of the catalyst was used.
The scope of complex 10 in RCEYM reactions was also
briefly evaluated (Table 2). Metathesis was amenable to
homopropargyl ether 6, as diene 8 was isolated in 72% yield
(entry 1). The method was also successfully applied to propargyl
ethers to afford 5- and 6-membered rings (entries 2-5). Dienes 29
and 31 were isolated in 58% and 72% yield, respectively. Diene
Overall the yields in Table 2 are somewhat lower than those
reported by Mori and co-workers for the same substrates.12 This
may be due to some catalyst decomposition (the ruthenium

4
Chem., Int. Ed. 2012, 51, 5062; e) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457.
dihydrides are quite air-sensitive). The precatalyst also requires a
sacrificial alkyne in the same quantity as the catalyst loading to
form the active vinylidene, which limits the overall yield (the
reported yields are not adjusted for the loss of alkyne to form the
vinylidene). Additionally, in many cases it was difficult to isolate
the pure diene products due to contamination by ruthenium
catalyst decomposition side products (difficulties in removal of
metal catalyst decomposition side-products from metathesis
reactions have been reported19), which required careful
chromatography to remove. This was especially problematic with
the more polar dienes (like 39 and 41), and accounts for the
significant differences in the NMR yields and the isolated yields.
Mori and co-workers did have to employ an atmosphere of
ethylene to achieve their higher yields, however, which was not
required for the ruthenium dihydride based catalysts. Attempts to
improve the yield of enyne metathesis for catalyst 10 by
performing the reaction under an ethylene atmosphere did not
result in an improved yield.
4.
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In summary, a new enyne metathesis catalyst system has been
developed based on a ruthenium dihydride precursor. This
catalyst system has been shown to be active in ring closing enyne
metathesis and was also capable of performing ring closing olefin
metathesis through use of a sacrificial alkyne. Experimental
evidence suggests that ruthenium vinylidene intermediate is the
active catalyst in this reaction. This hypothesis is further
supported by deuterium labeling experiments and olefin
metathesis activity in the presence of a terminal alkyne. This
work demonstrates that ruthenium dihydrides may access a
RCEYM mode of reactivity.
12.
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at (insert web address). This material
includes detailed experimental procedures and NMR data (1H and
13C spectra).
14.
15.
Acknowledgments
Support for the Syracuse University NMR facility was
provided by the National Science Foundation (CHE-1229345).
References and notes
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5
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Ruthenium Dihydride Complexes as Enyne
Metathesis Catalysts
Leave this area blank for abstract info.
Martin A. Dolan, Alexandre D. C. Dixon, John D. Chisholm* and Daniel A. Clark*

6
Highlights
• RuH2Cl2(PR3)2 complexes act as catalysts for
enyne metathesis.
• Mechanistic studies implicate a ruthenium
vinylidene as the active catalyst.
• Many good yields are obtained with 1,6 and 1,7-
enynes using these catalysts.