E- and Z-Selective Transfer Semihydrogenation of Alkynes Catalyzed by Standard Ruthenium Olefin Metathesis Catalysts

Article abstract of DOI:10.1021/acs.orglett.6b03254

Selective transfer semihydrogenation of alkynes to yield alkenes was achieved with commercial first and second generation Hoveyda-Grubbs catalysts and formic acid as a hydrogen donor. This catalytic system is distinguished by its selectivity and compatibility with many functional groups (halogens, cyano, nitro, sulfide, alkenes). The metathetic activity of the ruthenium catalysts may be utilized in tandem sequences of olefin metathesis plus alkyne reduction.

Full text of DOI:10.1021/acs.orglett.6b03254

Letter
pubs.acs.org/OrgLett
E- and Z‑Selective Transfer Semihydrogenation of Alkynes Catalyzed
by Standard Ruthenium Olefin Metathesis Catalysts
Rafał Kusy and Karol Grela*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, P.O. Box 58, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: Selective transfer semihydrogenation of alkynes to
yield alkenes was achieved with commercial first and second gen-
eration Hoveyda−Grubbs catalysts and formic acid as a hydrogen
donor. This catalytic system is distinguished by its selectivity and
compatibility with many functional groups (halogens, cyano, nitro,
sulfide, alkenes). The metathetic activity of the ruthenium catalysts
may be utilized in tandem sequences of olefin metathesis plus alkyne
reduction.
he Lindlar semireduction of alkynes1 is a long-standing
synthetic transformation, present in classical textbooks.2
knowledge, none of them use ruthenium alkylidene complexes,
commonly employed as olefin metathesis catalysts.10
T
Due to its well-established stereochemical course, Z selectivity is
the intrinsic feature of this transformation. The small amounts of
isomeric or over-reducted byproducts that sometimes accom-
pany the (Z)-alkenes are derived from secondary processes.2 The
formation of (E)-alkenes by catalytic hydrogenation is, however,
more difficult.3 Therefore, active research has been started in the
area of E-selective alkyne reductions, and some promising
catalytic systems have been very recently developed, employing
transition metal complexes in combination with hydrogen gas
or with various transfer hydrogenation agents. Two years
Our recent observation that ruthenium metathesis catalysts
in the presence of HCO2H and NaH form [Ru]−H species
capable of reduction of C−C double bond11 encouraged us
to translate this methodology to the reduction of triple bonds.
First, in a model hydrogenation reaction of diphenylacetyl-
ene (tolane, 1a)12 various ruthenium complexes were tested,
from the simplest ones to the contemporary alkylidene olefin
metathesis catalysts (Figure 1). In a typical run the addition of
substrate and internal standard (durene) solutions to a vessel
ago Furstner et al. reported on the revolutionary (E)-selective
̈
semihydrogenation of alkynes employing commercial complex
[Cp*Ru(cod)Cl] under a H2 pressure of 10 bar.3 This system is
characterized by excellent E/Z selectivity and a wide scope
of alkyne substrates.3 More recent examples of a triple bond
semireduction catalyzed by a ruthenium complex were pub-
lished by Mandkad (2015)4 and Lindhardt (2016).5 The
first publication refers to application of heterobimetallic
(IMes)Ag−RuCp(CO)2 in the reduction of tolanes. The second
one describes semihydrogenation of tolanes and terminal aryl-
alkynes with the use of commercial Ru(PPh3)3(CO)(H)Cl
under low H2 pressure. The quest for more environmentally
benign and inexpensive catalysts is another recently observed
trend. In 2014, Liu et al. described an interesting approach for
E-selective tolane reduction with Na2S and water.6 In 2013,
Milstein et al. proposed an innovative E-selective semireduction
of various internal alkynes as well as phenylacetylene by means of
a newly synthesized iron pincer complex under H2 pressure.7
It must be stressed that the compatibility of the recently
developed catalytic systems with reducible functional groups
(such as NO2) is high in many cases, and the sometimes observed
over-reduction of a triple bond to a single bond can usually be
avoided. However, despite the enormous progress in alkyne
semireduction, only a few catalyst systems can allow switch-
able selectivity leading to either the (E)- or (Z)-olefin isomer
according to ligand alteration,8,9 and to the best of our
Figure 1. Selected ruthenium complexes tested in this study.
Received: October 30, 2016
© XXXX American Chemical Society
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containing a ruthenium complex and NaH (0.2 equiv) was
followed by addition of HCO2H (50 equiv). The conditions were
similar to those previously used by us for olefin reduction,11 with
the difference that the reduction of acetylene 1a was carried out
in an open Schlenk tube under argon, not in a sealed ampula
under pressure.11
Again, THF was chosen as the best solvent, and the progress
of the reaction was analyzed by GC. In most cases, good to
complete conversion of 1a was observed; however, in addition to
the expected stilbenes, other products were also obtained in
some cases (Table 1). Namely, the use of Ru(PPh3)3Cl2 and
complexes were chosen for further studies, as they showed both
good reactivity and high Z- and E-selectivity (Table 1).
During optimization of the hydrogenation reaction conditions,
we found that the amount of added sodium hydride affects the
conversion of the starting material and the selectivity of the
reaction.11 In the case of 0.8 equiv of NaH, the reaction is
complete after 0.5 h while the conversion of 1a in the reaction
conducted without NaH reached only 10%. On the other hand,
use of NaH in amounts greater than 0.2 equiv led to worse
selectivity (see the Supporting Information for details). There-
fore, we decided to use 0.2 equiv of the base and carry out
the reaction for the time required to obtain maximal conversion
(6−24 h).
Table 1. Screening of Ruthenium Catalysts
To understand better the relation between Hoveyda−Grubbs
catalyst generation and selectivity of the semireduction, we
examined the consumption of a substrate and formation of
products according to the time of reaction. The results are
presented in the form of molar fraction changes with time
(Figures 1 and 2). Based on the results, we can state that
Figure 2. Reduction of diphenylacetylene 1a with Hoveyda−Grubbs
first generation catalyst. Conditions: 0.02 equiv of Hov I, 0.2 equiv of
NaH, 50 equiv of HCO2H, 80 °C, THF.
(Z)-stilbene seems to be in all cases the initial product of the
reaction that undergoes, with time, isomerization13 to more
thermodynamically stable (E)-stilbene (Scheme 1). In the case of
a
Conditions: 0.02 equiv of catalyst, 0.2 equiv of NaH, 50 equiv of
b
HCO2H, 80 °C, 6 h, THF. Two additional products, substantial
decomposition of HCO2H. Conversion and product distribution were
c
determined by GC analysis.
Scheme 1. Proposed Reduction−Isomerization Sequence
Ru(PPh3)3(CO)(H)Cl resulted in formation of additional
products and intensive decomposition of HCO2H to CO2
and H2. The screening indicated that the ruthenium−alkylidene
complexes (entries 5−17) led to more clean reactions. As a
consequence, we focused our efforts on the use of commercial
Ru olefin metathesis catalysts for semireduction.
The results indicated that first generation ruthenium−
benzylidene complexes, containing aliphatic phosphine ligands
(PCy3), favor production of (Z)-stilbene (entries 5, 8, 10, 15)
while the second generation benzylidene complexes, bearing
the N-heterocyclic (NHC) ligand, promote production of
(E)-stilbene (entries 6, 9, 11, 17). The third generation catalyst
Gru III showed low selectivity (entry 7). The standard
indenylidene-based complexes M1 and M2 lead to lower
conversion or selectivity (entries 12, 13) but followed the
general trend. Interestingly, complex M10 gave predominantly
the (E)-stilbene, while belonging formally to the first generation
of Ru metathesis catalysts. The second PPh3-containing catalysts
tested by us, M20, gave, in contrast, a relatively high content
of the (Z)-isomer. Based on the results of this preliminary
screening, the most simple and very stable Hov I and Hov II
the less active first generation Hoveyda−Grubbs catalyst, this
process may be stopped at the first step, to afford the (Z)-product
with good selectivity (Figure 2). In the case of the more reactive
second generation Hoveyda−Grubbs catalyst, (Z)-stilbene is
also an initial product (Figure 3), but during the first hour of the
reaction it was almost completely isomerized to the (E)-product
(Figure 3).
To find the factor responsible for the isomerization process we
carried out three separate experiments. In the first one, a THF
solution of (Z)-stilbene was heated in the presence of 50 equiv
of HCO2H at 80 °C. In the second one, 0.02 equiv of Hov II
was used together with only 0.02 equiv of HCO2H. The third
experiment was similar to the previous one, but HCO2H was left
out. After 24 h, the substrate (Z)-2a remained intact in the
first case, while in the second and third reaction (Z)-2a was
completely isomerized to (E)-2a. Based on the above results,
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Table 2. Substrate Scope and Functional Group Tolerance of
the Title Reaction
Figure 3. Reduction of diphenylacetylene 1a with Hoveyda−Grubbs
second generation catalyst. Conditions: 0.02 equiv of Hov II, 0.2 equiv
of NaH, 50 equiv of HCO2H, 80 °C, THF.
it seems probable that the ruthenium complex in both the
presence and absence of HCO2H is the factor responsible for
isomerization of (Z)-stilbene to its (E)-isomer. This intrigu-
ing reactivity of olefin metathesis complexes encouraged us to
investigate the scope of the method in more detail. As can be seen
from the results compiled in Table 2, Grubbs−Hoveyda catalysts
(0.02 equiv) in the presence of HCO2H (50 equiv) and NaH
(0.2 equiv) in THF allowed an assortment of substrates to be
reduced by HCO2H (50 equiv) with excellent E/Z selectivity
control. In the presence of the Hov I catalyst the semi-
hydrogenation proceeded cleanly to afford (Z)-olefins in very
good yields and selectivity (Table 2. entries 1−3). To obtain
(E)-products, the Hov II complex was used instead (Table 2,
entries 4−11). The observed high E-selectivity renders the
latter method to be stereocomplementary to the classical Lindlar
reduction.
Importantly, substrates containing various functional groups,
both electron-donating and -withdrawing, are tolerated (Table 2).
For example, there was no sign of protodebromination of the aryl
bromide fragment of tollane 1c (Table 2, entries 3 and 8), which
offers additional flexibility, as compared with Pd-based Lindlar
semihydrogenation methods. Even a thioether moiety did not
poison the catalyst, as can be observed from the case of tollane 1h
bearing a 1,3-dithiane ring that underwent transfer hydro-
genation without deprotection or desulphurization (Table 2,
entry 11). Moreover, a reducible nitro group remained intact
(Table 2, entries 9). However, in the case of a nitrile group,
0.03 equiv of Hov II catalyst had to be used, and the reaction
was carried out for 48 h to obtain full conversion with a trace of
amine derivative (Table 2, entry 10). The possible reason why
this substrate requires a higher catalyst loading and longer
reaction time may be due to coordination of this functional
group to a ruthenium complex.14 It shall be noted that many,
otherwise excellent systems for alkyne semireduction are not
compatible with the nitro group.7 Furthermore, the reduction
of aryl-alkyl alkynes 1i−1k and cycloalkyne 1l with the use of
Hov II led to formation of corresponding E-alkenes (Table 2,
entries 12−15), serving as proof that our catalytic system has a
wider scope of potential applications than just substituted
diphenylacetylenes. Lower yields in those cases were caused by
overreduction of alkynes and formation of other unidentified
products. We found our catalytic system incompatible with ter-
minal alkynes.
a
b
Only major isomer of the product was shown. 0.03 equiv of Hov II,
c
d
e
f
g
24 h. 24 h. 1 h. 4.5 h. 2 h. 0.04 equiv of Hov II, 3 h, 90 °C.
h
Method A: 0.02 equiv of Hov I, 0.2 equiv of NaH, 50 equiv of
HCO2H, 80 °C, 24 h, THF. Method B: 0.02 equiv of Hov II, 0.2 equiv
of NaH, 50 equiv of HCO2H, 80 °C, 6 h, THF. Isolated yield. Ratio of
crude determined by GC analysis. 6% of formylated amine derivative
i
j
k
was formed. GC yield.
Procedures commonly known as “one-pot” processes have
found numerous applications in laboratories and industry.15
This technique allows for the more effective use of solvents and
other materials than in traditional stepwise procedures and can
allow the synthesis of highly complex products by using simple
substrates.15 Owing to the current global interest in one-pot
transformations, and being aware of the high metathetical activity
C
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ORCID
of Hoveyda−Grubbs complexes used by us in alkyne reduction,
we decided to test a model one-pot metathesis−semireduction.
To do so, we carried out a single-pot reaction of 1j which
consisted of ring closing metathesis (RCM) and triple C−C
bond hydrogenation (Scheme 2). After completion of RCM,
Karol Grela: 0000-0001-9193-3305
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 2. One-Pot RCM−Semireduction and Ortep Drawing
of Product (E)-2m
The authors are grateful to the National Science Centre (Poland)
for the NCN Opus Grant No. UMO-2013/09/B/ST5/03535.
We wish to thank Paweł Szczepanik (Institute of Organic
Chemistry, PAS) for providing us with tolanes 1b−1g.
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formic acid and sodium hydride were added into the reaction
mixture to convert Hov II into the catalytic system for
semireduction,11 leading to product (E)-2m in a total yield of
49% after two steps. Although product (E)-2m can be obtained
by other means (in two or more steps), this example is useful to
demonstrate the high selectivity of this reduction system.
Notably, the C−C double bond formed during the RCM
step did not undergo further reduction to a single bond or
isomerization. The latter transformation (a double bond shift) is
a rather common process, triggered by decomposed Ru olefin
metathesis catalysts.16
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Hoboken, NJ, 2014.
Outlined herein are our preliminary results on a ligand-
controlled semihydrogenation of alkynes to form either (E)- or
(Z)-alkenes using classical Hoveyda−Grubbs olefin metathesis
catalysts and formic acid as a safe hydrogen source. Importantly,
the second generation of benzylidene ruthenium complexes
led almost exclusively to (E)-selective alkyne hydrogenation,
rendering this method to be stereocomplementary to the
classical Lindlar reduction. The metathetic capability of the
ruthenium complexes used by us for the reduction may be also
utilized in tandem sequences composed of olefin metathesis−
alkyne reduction. As the developed system operates under mild
conditions and tolerates a host of sensitive functional groups we
believe that it holds great promise for future applications in
target-oriented syntheses.
́
(11) Zielinski, G. K.; Samojłowicz, C.; Wdowik, T.; Grela, K. Org.
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during a palladium-catalyzed hydrogen-transfer reaction with 25%
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(14) In the case of Milstein’s Fe-based hydrogenation catalyst, it was
also observed that diarylacetylenes bearing CN groups require a higher
catalyst loading and longer reaction times to reach full conversion to the
alkene. See ref 8.
ASSOCIATED CONTENT
* Supporting Information
(15) (a) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248
■
S
(21−24), 2365−2379. (b) Zielinski, G. K.; Grela, K. Chem. - Eur. J. 2016,
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22 (28), 9440−9454.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03254.
(16) (a) Schmidt, B. Chem. Commun. 2004, No. 6, 742−743.
(b) Schmidt, B. J. Org. Chem. 2004, 69 (22), 7672−7687.
Crystallographic data (CIF)
Full experimental details, copies of spectral data, X-ray
crystal structure (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: karol.grela@gmail.com.
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DOI: 10.1021/acs.orglett.6b03254
Org. Lett. XXXX, XXX, XXX−XXX