Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

Article abstract of DOI:10.1021/acs.joc.9b02721

Selective direct ruthenium-catalyzed semihydrogenation of diaryl alkynes to the corresponding E-alkenes has been achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands, and affords the desired products in > 99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem semihydrogenation-alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives.

Full text of DOI:10.1021/acs.joc.9b02721

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Article
Ruthenium-Catalyzed E-Selective Alkyne Semi-
Hydrogenation with Alcohols as Hydrogen Donors
Andreas Ekebergh, Romain Begon, and Nina Kann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02721 • Publication Date (Web): 06 Feb 2020
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The Journal of Organic Chemistry
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Ruthenium-Catalyzed E-Selective Alkyne Semi-Hydrogenation with
Alcohols as Hydrogen Donors
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Andreas Ekebergh, Romain Begon and Nina Kann*
Chemistry and Biochemistry, Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-
41296 Göteborg, Sweden
semi-hydrogenation, ruthenium, alkyne, E-alkene, alcohol, hydrogen borrowing, amine alkylation
ABSTRACT: Selective direct ruthenium-catalyzed semi-hydrogenation of diaryl alkynes to the corresponding E-alkenes has been
achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands
and affords the desired products in >99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl
alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem
semi-hydrogenation – alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives.
A few accounts of direct ruthenium-based E-selective semi-
hydrogenations of alkynes have also been published in the
last decade (Scheme 1).10 Several of the reported ruthenium
systems require elevated temperatures (145-180 °C),10c, 10h or
stoichiometric or excess amounts of organic acids (1-50
equivalents).10c, 10k Despite displaying good substrate scope in
the presence of other reductive-sensitive functional groups,
these harsh reaction conditions could limit the utility of these
methods. Milder methods for semi-hydrogenations based on
ruthenium have recently been described.10d, 10j Fürstner and
co-workers used high pressures of dihydrogen (10 bar) with
silver triflate as additive at ambient temperatures,10d or
propargylic alcohols as substrates at lower pressures (1
bar),10l while Lindhardt recently published a method
proceeding at 45 °C with dihydrogen generated in situ in a
closed two-chamber system.10j Djukic et al. have shown that
-chlorido, -hy droxobridged ruthenacycles can effect the
hydrogenation of triple bonds using isopropanol as the
hydrogen donor at 90 °C,10b while Gelman has reported an
elegant semi-hydrogenation of alkynes involving ligand-
metal cooperation as the mode of action, using a ruthenium
catalyst and a mixture of formic acid and sodium formate as
the hydrogen source.10i
Introduction
The alkene motif is present in a variety of important
molecules, including natural products, pharmaceuticals and
fragrances (Figure 1).1 Stereoselective installation of this
functionality therefore remains central to organic synthesis.
Semi-hydrogenation of alkynes is a natural synthetic
transformation to obtain alkenes. However, E-selective
alkyne semi-hydrogenations have historically been more
difficult to achieve than Z-selective. The former
transformation has typically been limited to alkynes bearing
alcohols, amines or ketones in the propargylic position,
generally requiring stoichiometric reagents,2 or proceeding
via two-step methods such as trans-hydrosilylation followed
by protodesilylation.3
HO
CO2H
OH
OH
trans-anethole
(fragance)
O
O
COOMe
OH
F
N
HO
misoprostol
(anti-ulcer drug)
HO
OH
fluvastatin
resveratrol
Scheme 1. Ruthenium-catalyzed methods for alkyne semi-
hydrogenation to E-alkenes.
(cardiovascular agent)
(found in grapes)
Figure 1. Selected E-alkenes.
Lately, hydrogenation based on homogeneous transition
metal catalysis has begun to offer a remedy to these
limitations.2 For example iron,4 cobalt,5 nickel,6 palladium,7
manganese,8 and iridium9 have been used to obtain alkenes
from alkynes with E-selectivity. In particular, an iridium-
catalyzed method for alkyne semi-hydrogenation recently
reported by Yang et al. deserves highlighting,9a as it allows
the selective formation of either the E- or the Z-alkene isomer
simply by adding a bulkier ligand (COD) to the reaction
system in the latter case. In addition, an inexpensive and
sustainable alcohol (ethanol) is used as the hydrogen source.
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the reactivity of isopropyl alcohol could be greatly enhanced
historically
preferred
a) Previous reports:
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by introducing a methoxy group in the 1-position, generating
a substantial amount of bibenzyl. Control experiments were
also performed. Excluding base from the reaction
significantly lowered the efficiency, affording 13% of (Z)-2a
and no other products. The alcohol and catalyst, as expected,
proved to be essential to the reaction, with no products
formed in their absence.
Z
E
R'
"H2"
R
R'
+
R
R'
R
Ru-catalysis
hydrogen source: H2, NH3•BH3, Bu3N, DMF/H2O, HCO2H, ROH
While benzyl alcohol outperformed the other hydrogen
donors, the generation of reactive benzaldehyde in situ could
under some circumstances be problematic due to its potential
reactivity with nucleophiles. Isopropyl alcohol, on the other
hand, forms acetone, which is less prone to adduct formation
with nucleophiles. Additionally, compared to benzyl alcohol
and benzaldehyde, both isopropyl alcohol and acetone can be
easily removed through evaporation, thus expediting the
purification of the product. Further optimization was thus
performed using isopropyl alcohol as the hydrogen donor,
aiming to improving the E/Z-selectivity and yield.
b) This study:
9
• E-selective • alcohols as hydrogen donors
• simple Ru catalyst • no ligands or acid additives necessary
• mild conditions • tandem semi-hydrogenation amination
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
By adding D2O, this procedure could also be applied towards
deuterium labelling.
While conducting
a ruthenium catalyzed ‘borrowing
hydrogen’ reaction involving alcohols and amines in the
presence of an alkyne functionality,11 we noticed that small
amounts of the corresponding alkene were formed. We
envisioned that a transfer hydrogenation between the alcohol
and the alkyne competed with the borrowing hydrogen
reaction to a minor extent. Indeed, in 1981, Shvo and co-
workers presented a ruthenium catalyzed oxidative ester
formation from alcohols using diphenylacetylene as a
hydrogen acceptor.10a Despite recent reports on alkyne semi-
hydrogenations, the scope of ruthenium catalyzed transfer
hydrogenation between alcohols and alkynes has, to the best
of our knowledge, not been investigated in detail.10b We
herein present a relatively mild semi-hydrogenation of
alkynes which can be performed without the necessity of
external ligands or stoichiometric amounts of
organic/inorganic acids or bases. The procedure performs
well with diaryl acetylenes and is experimentally facile, using
only commercially available reagents and without the need
for any special equipment.
Scheme 2. Screening of alcohols as hydrogen donors for Ru-
catalyzed alkyne hydrogenation.a
Ru3(CO)12
(3.3 mol%)
ROH (10 equiv)
(Z)-2a
+
tBuOK (1 eq.)
toluene,
100 °C, 24 h
2a
(E)-
1a
+
3
Results and Discussion
For the initial investigation of the transfer hydrogenation
between alcohols and alkynes, diphenylacetylene (1a) was
used as a model substrate (Scheme 2). A selection of different
alcohols were screened for efficiency, E/Z-selectivity and
their ability to avoid over-reduction. The reaction was
performed in the presence of a simple ruthenium catalyst,
Ru3(CO)12, and initially with stoichiometric amounts of
tBuOK as base, using toluene as the solvent and heating the
reactions in a heating block. Experiments were analyzed by
1H NMR using 2,5-dimethylfuran as internal standard.12 Of
the screened hydrogen donors, benzylic alcohols (benzyl and
furfuryl alcohol, 1-phenylethanol) stood out both in terms of
selectivity and efficiency. In particular, benzyl alcohol
produced E-stilbene ((E)-2a) with 100% selectivity over Z-
stilbene ((Z)-2a) whilst only generating ~ 2% bibenzyl (3) via
over-reduction. A number of other alcohols also displayed
good compatibility with the reaction. Cyclopentanol
generated the semi-hydrogenation product in good yields,
with only minor overreduction, while longer non-cyclic
secondary aliphatic alcohols (2-butanol, 3-pentanol) reacted
sluggishly. Isopropyl alcohol and ethanol both showed a
good conversion to alkene, while the more hindered
neopentyl alcohol and glycerol reacted slowly. Interestingly,
aNMR yield (2,5-dimethylfuran as internal standard). Reactions
were heated in a heating block.
In addition to Ru3(CO)12, nine other commercially available
ruthenium catalysts were screened using isopropyl alcohol as
the hydrogen donor (Table 1). The reactivity of the catalysts
varied from very low when using RuCl3 (entry 2),
Cp*RuCl(COD) (entry 5) or the Shvo catalyst (entry 9 and
Figure 2), to being higher but unselective for the semi-
hydrogenation product when RuCl2(PPh3)3 was employed
(entry 7). The Grubbs 1st generation catalyst (Figure 2) gave
the fully reduced bibenzyl product 3 with nearly complete
selectivity in a good yield (entry 4). However, our interest lay
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in the selective semi-hydrogenation to form the (E)-2a. In this
5 mol% catalyst (entry 3). RuCl2(DMSO)4/iPrOH was also
evaluated, but displayed a much slower reaction rate.
Reducing the amount of catalyst, base and alcohol
dramatically reduced the yield within the investigated time
frame of 24 h (entries 7-10).
1
2
3
4
5
6
7
8
context, catalyst RuCl2(DMSO)4 displayed good properties,
with a combined yield of 91% and 6:1 in terms of the E/Z
selectivity (entry 3). RuCl(CO)H(PPh3)3 also performed well,
affording only (E)-2a in a good yield, albeit with some
concomitant over-reduction to 3 (entry 6). Viable catalysts
for the E-selective semi-hydrogenation of diphenylacetylene,
using isopropyl alcohol as the hydrogen donor, were thus
Table 2. Optimization of reaction conditions using
phenylacetylene (1a).a
entry
catalyst
tBuOK
(equiv)
yieldb
2 (%)
>99
93
E:Z
found
to
be
Ru3(CO)12,
RuCl2(DMSO)4
and
RuCl(CO)H(PPh3)3. RuCl2(DMSO)4 was selected for further
studies when using isopropyl alcohol as the hydrogen donor.
2
(mol% Ru)
9
1c
2c
Ru3(CO)12 (10)
Ru3(CO)12 (2)
1
1
1:0
1:0d
1:0
10
11
12
13
3c
4c
Ru3(CO)12 (5)
1
89
Ru3(CO)12 (2)
0.2
0.2
0.2
1
>99
17
1:0
Table 1. Catalyst screening in the Ru-catalyzed reduction of
phenylacetylene (1a).a
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5c,e
6c,f
7g
Ru3(CO)12 (2)
1:2.4
2.3:1
6:1
Ru3(CO)12 (2)
79
entry
catalyst
yieldb
2 (%)
30
4
E:Z
2
yieldb
RuCl2(DMSO)4 (10)
RuCl2(DMSO)4 (2)
RuCl2(DMSO)4 (2)
RuCl2(DMSO)4 (2)
91
3 (%)
3
8g
9g
10e,g
1
19
1:1
1
2
[Ru(p-cymene)Cl2]2
RuCl3
1:1
3:1
6:1
1:0
3:1
1:0
1:0
8:1
7:1
1.5:1
0.2
0.2
19
1:1
0
5
4:1
3
4c
RuCl2(DMSO)4
Grubbs catalyst
Cp*RuCl(COD)
RuCl(CO)H(PPh3)3
RuCl2(PPh3)3
91
3
10
75
o
aReactions performed at 100 °C (heating block) with 10
equivalents hydrogen donor for 24 h unless otherwise indicated.
Only trace bibenzyl (3) formed unless otherwise indicated. bNMR
5
4
c
yield (2,5-dimethylfuran as internal standard). Benzyl alcohol as
6
69
28
18
8
13
39
o
hydrogen donor. d4% bibenzyl (3) formed. e2 equivalents hydrogen
donor. fReaction performed at 80 °C. gIsopropyl alcohol as
hydrogen donor.
7
8
9c
Cp*RuCl (PPh3)3
Shvo catalyst
o
The optimized conditions for Ru3(CO)12/benzyl alcohol
(Method A) were then applied to a series of alkynes (1a-n,
Scheme 3) to investigate the scope. Diaryl acetylenes with
varying electronic properties were well tolerated and formed
their corresponding hydrogenated E-isomers selectively, with
close to quantitative conversion (as determined by 1H NMR)
and high isolated yields (compounds 2a-f). Electron rich
compounds such as 1c reacted slightly slower and longer
reaction times were needed to achieve full conversion.
Primary amines and pyridines (1g-i) proved to be more
challenging substrates. The hydrogenation of the p-amino
derivative proceeded sluggishly under the standard
conditions. Increasing the catalytic loading fourfold gave a
satisfactory hydrogenation yield, accompanied, however, by
the formation of substantial amounts of another compound
(Scheme 4). Interestingly, further analysis showed that this
compound resulted from a hydrogen borrowing process13
between benzaldehyde, formed in situ from the benzyl
alcohol hydrogen donor and the primary amine, to form an
intermediate imine that could be reduced to the
corresponding amine 4 (Scheme 4) using a second equivalent
of hydrogen. The fact that a concomitant semi-hydrogenation
− amine alkylation process is feasible is not surprising, as
Ru3(CO)12 has been employed for the direct amination of
alcohols via hydrogen borrowing under similar conditions.14
This tandem process could potentially be applied towards the
synthesis of resveratrol derivatives such as 5, reported as a
promising lead compound for the treatment of Alzheimer’s
disease.15 Switching to different reaction conditions, utilizing
iPrOH as hydrogen donor with RuCl2(DMSO)4 as the catalyst
10
Ru3(CO)12
74
3
aReaction and conditions as in Scheme 2, but with different
catalysts. Isopropyl alcohol was used as the hydrogen donor.
b
Catalyst amount corresponds to 10 mol% Ru. NMR yield (2,5-
dimethylfuran as internal standard). cSee Figure 2.
H
P(Cy)3
O
O
Ph
Ph
Ph
Cl
Ph
Ph
Ru
Ph
Ph
Ph
Cl
Ru
OC
Ru
Ph
H
P(Cy)3
CO
OC
CO
Grubbs 1st generation
catalyst
Shvo catalyst
Figure 2. Structures of the Grubbs 1st generation and Shvo
catalysts.
With two catalyst systems in hand, i.e. Ru3(CO)12/benzyl
alcohol and RuCl2(DMSO)4/iPrOH, further studies
concerning the loading of catalyst, base and hydrogen donor
were performed (Table 2). For Ru3(CO)12/benzyl alcohol,
using a catalyst amount corresponding to 2 mol% Ru and
reducing the amount of base to 0.2 equivalents did not affect
the yield (entries 1 and 4), while lowering the amount of
alcohol (entry 5) or temperature (entry 6) had a negative
effect on the yield as well as the E/Z selectivity. Interestingly,
reducing the amount of catalyst while maintaining the base at
1 equivalent decreased the yield of the alkene (entry 2).
Hence, the activity of the catalyst is related to the relative
amount of base. The same behavior was observed when using
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(Method B), suppressed the competing hydrogen borrowing higher catalytic loading and also a longer reaction time, but
1
2
3
4
5
6
7
8
reaction, allowing isolation of alkene 2g in a moderate yield.
The more sterically challenging ortho-amine could be
reduced using Method A, but required a higher catalytic
loading to proceed (compound 2h). In this case, the hydrogen
borrowing product was not observed, most likely owing to
the more hindered position of the amino group in the
substrate. Similarly to the other nitrogen-containing
compounds, 3-(phenylethynyl)pyridine also required a
Scheme 3. Scope of the semi-hydrogenation reaction.a
afforded 2i in a high NMR yield. The lack of reactivity is
most likely due to deactivation of the catalyst through
coordination by the nitrogen. This could also explain the lack
of reports on the ruthenium-catalyzed semi-hydrogenation of
aniline-containing compounds. The protons ortho to the
nitrogen displayed broad signals in 1H NMR after completion
of the reaction, indicating coordination. The stability of this
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Method A: Ru3(CO)12 (0.66 mol%),
tBuOK (20 mol%), benzyl alcohol (10 equiv),
toluene, 100 °C, 24h
H
R'
R
R'
R
Method B: RuCl2(DMSO)4 (10 mol%),
tBuOK (50 mol%), iPrOH (10 equiv),
toluene, 100 °C, 24h
1a-n
H
2a-n
OMe
Cl
CF3
2a, (>99%) 88%
2b, (>99%) 93%
2c, (>99%) 85%
2d, (>99%) 89%
NH2
CF3
Cl
MeO
NH2
MeO
2e, (>99%) 87%
2f, (>99%) 83%
2g, (80%,
/
E Z
66/14) 51%b
S
2h, (59%,
/
45/14) 34%c
E Z
H
N
N
Cl
Fe
E Z
/
89/10) 76%d
2i, (>99%,
/
E Z
70/30) 48%c
2j, (75%) 56%b
2k, (>99%,
2l, (60%) 49%
O
O
OH
2n, (52%) 44%b,e
2m, (>99%) 88%
Limitations: alkynes affording <25% yield
OH
NO2
OH
MeO
aPrepared using method A unless otherwise stated; reactions were heated in a heating block. See SI for deviations in terms of reaction
time. Yields in parentheses refer to NMR yields of E-alkene (for 2g-i and 2k a mixture of E and Z alkenes). Isolated yields refer to E alkene
b
only. Prepared using Method B. See SI for deviations in terms of reaction time. Product 2n is a result of semihydrogenation with concomitant
reduction of the carbonyl group. c3.33 mol% Ru3(CO)12 used. dProduct contains 3% of the (Z)-isomer.e20 mol% RuCl2(DMSO)4 used.
interaction was further validated as it was maintained even
after column chromatography on silica. The ruthenium could
be removed by chromatography on amine-functionalized
silica, supplying pure semi-hydrogenation product with some
loss in yield due to the more elaborate purification required.
Other heterocyclic alkyne substrates were more successful,
with indole- and thiophene-derivatives 2j and 2k formed in
56% and 76% yields, respectively. A ferrocenyl-substituted
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E-alkene (2l) could be obtained in moderate yield, while
carbon bond formation instead of amine alkylation. Method
B instead effected concomitant alkyne semi-hydrogenation
and transfer hydrogenation of the ketone, producing alcohol
2n in a moderate yield. In terms of limitations of the reaction,
alkyl/aryl substituted alkynes as well as dialkylacetylenes
were unsuccessful, showing both low reactivity as well as the
formation of byproducts. Analysis of the crude products by
1H NMR showed that while some alkene was formed in the
reaction, double bond isomerization had also occurred,
1
2
3
4
5
6
7
8
appending an ester substituent to diphenyl acetylene was
unproblematic (2m), although transesterification occurs if the
corresponding methyl ester is used as precursor instead.
Exchanging the ester for a ketone gave interesting results.
Method A afforded the benzylated ketone 6 (Fig. 3), instead
of the expected semi-hydrogenation product. This product is
most likely also the result of a hydrogen borrowing-type
mechanism (as for 4), but in this case involving carbon-
Scheme 4. Tandem alkyne semi-hydrogenation and direct amine alkylation.
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Method A
Ru3(CO)12
NH2
H
N
tBuOK
NH2
H
2g
H
H
H
Ph
OH
Ph
O
HO
Ru3(CO)12
H
N
tBuOK
H
N
N
O
H
H
H
5
4, 30%
O
Ph HO
Ph
O
O
H
6, 35%
H
Figure 3. Product of tandem alkyne semi-hydrogenation and
ketone alkylation (Method A).
resulting in a mixture of products. In addition, while a p-CF3
substituent on diphenylacetylene was well tolerated (2d), the
corresponding p-NO2 compound afforded
a complex
mixture, where some concomitant reduction of the nitro
group had taken place. Terminal alkynes such as 1-ethynyl-
4-methoxybenzene afforded a complex mixture, with only
trace amounts of products.
The reaction could be monitored over time using 1H NMR,
which revealed an initial hydrogenation to form the Z-isomer
that underwent an isomerization process to the E-isomer
(Figure 4). This observation is in line with previous
reports.10c, 10k, 16
Figure 4. Compound distribution over time.
The isomerization was further investigated by subjecting
cis-stilbene to the standard reaction conditions in the
presence of deuterated benzyl alcohol (Bn-OD). Z-Stilbene
((Z)-2a) was isomerized into E-stilbene ((E)-2a) under these
conditions, but without incorporation of deuterium (Scheme
5). This observation differs from the recent study by
Lindhardt and co-workers,10j in which they found that
isomerization of (Z)-2a in presence of a ruthenium catalyst
and D2 results in incorporation of deuterium at the alkenylic
positions. We further found that the isomerization to (E)-2a
occurred in the presence of the catalyst alone. These results
indicate that the isomerization process does not proceed via
a hydrogenation/rotation/β-hydride elimination route. No
isomerization was observed when omitting the catalyst while
including the other reactants. Both benzaldehyde and benzyl
benzoate were observed as side products after the transfer-
hydrogenation reaction. Benzyl benzoate is likely formed via
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a second reaction between benzaldehyde and benzyl alcohol
90/82 melting point apparatus and are uncorrected. IR spectra
with subsequent oxidation, as previously reported by Shvo.10a
were recorded with a PerkinElmer Spectrum ONE FT-IR
spectrometer using KBr pellet sample preparation. High-
resolution mass determinations were obtained with an
Agilent QTOF 6520 with Infinity UHPLC and electrospray
ionization.
1
2
3
4
5
6
7
8
Scheme 5. Investigation of the isomerization process.
H
General procedure for the preparation of internal
alkynes 1b and 1d-n via Sonogashira reaction. Arylhalide,
H
Ru3(CO)12 (0.66 mol%)
(E)-2a (75%)
t-BuOK (0.2 eq.)
bis(triphenylphosphine)palladium(II)
dichloride
H
H
C6H5CH2OH/D (10 eq.)
(Pd(PPh3)2Cl2) and copper(I) iodide (CuI) (see each
compound for amounts) were transferred to a dry 20 mL
Biotage microwave reaction vial equipped with a cross-
shaped magnetic stirring bar. The vial was sealed using a cap
with septum, evacuated of air and refilled with argon (3
cycles). The alkyne and dry deoxygenated Et3N were
thereafter transferred to the vial. The obtained mixture was
further deoxygenated by bubbling argon through for 5 min
while stirring. The argon inlet was removed and the reaction
was heated in a Radleys HeatOn™ block to 80 °C for
indicated amount of time. The reaction was cooled to room
temperature and concentrated under reduced pressure. The
crude product was taken up in approximately 5 ml CH2Cl2
and the slurry was transferred to a 3g Biotage KP-Sil samplet.
After allowing the samplet to dry it was transferred to a 25 g
column and purified by flash chromatography.
1-Methoxy-4-(phenylethynyl)benzene (1b).17 The reaction
was performed according to the general procedure using 4-
iodoanisole (1.17 g, 5.0 mmol), Pd(PPh3)2Cl2 (105 mg, 0.15
mmol), CuI (28 mg, 0.15 mmol), phenylacetylene (0.81 ml,
7.4 mmol) and Et3N (13 ml). Flash chromatography gradient:
Petroleum ether/EtOAc 1:0 -> 95:5 (10 column volumes) ->
95:5 (10 column volumes). Product 1b was obtained as a light
orange crystalline solid (991 mg, 95%): 1H NMR (400 MHz,
CDCl3) δ 7.54 – 7.49 (m, 2H), 7.47 (XX’ signal of AA’XX’
spin system, 2H), 7.37 – 7.30 (m, 3H), 6.88 (AA’ signal of
AA’XX’ spin system, 2H), 3.83 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 159.7, 133.2, 131.6, 128.4, 128.1, 123.7,
115.5, 114.1, 89.5, 88.2, 55.5.
1-(Phenylethynyl)-4-(trifluoromethyl)benzene (1d).18 The
reaction was performed according to the general procedure
using 1-iodo-4-(trifluoromethyl)benzene (554 mg, 2.0
mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), CuI (7.6 mg, 0.04
mmol), phenylacetylene (0.26 ml, 2.4 mmol) and Et3N (6 ml).
Flash chromatography gradient: Petroleum ether/EtOAc 1:0
-> 1:0 (5 column volumes) ->85:15 (15 column volumes).
Product 1d was obtained as a white crystalline solid (512 mg,
>99%): 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.59 (m, 4H),
7.58 – 7.52 (m, 2H), 7.41 – 7.35 (m, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 132.0, 131.9, 130.0 (q, J = 32.7 Hz), 129.0,
128.6, 127.3 (q, J = 1.5 Hz), 125.4 (q, J = 3.8 Hz), 124.1 (q,
J = 272.2 Hz), 122.7, 91.9, 88.1.
9
toluene, 100 °C, 24 h
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60
H
H
(Z)-2a (25%)
H
(Z)-2a
Ru3(CO)12 (0.66 mol%)
toluene, 100 °C, 24 h
H
(E)-2a (100%)
Conclusion
In conclusion, a methodology for the selective semi-
hydrogenation of diaryl alkynes to E-alkenes was developed,
involving the use of a simple Ru-catalyst, a low catalyst
loading, ligand-free conditions and alcohols as the source of
hydrogen. While benzyl alcohol gave the most favourable E-
selectivity and conversion, renewable alcohols such as
furfuryl alcohol could also be applied as hydrogen donors
with good results. A tandem semi-hydrogenation − amine
alkylation reaction, the latter via hydrogen borrowing, was
also demonstrated, using 4-(phenylethynyl)aniline (1g) as the
substrate. Reaction monitoring indicates that the high E-
selectivity in the semi-hydrogenation is due to isomerization
of initially formed Z-alkene by the catalyst, rather than a
result of the semi-hydrogenation process itself.
Experimental Section
General Remarks. All reactions were carried out under
argon atmosphere with dry solvents in oven dried glassware,
unless otherwise noted. Toluene, triethylamine (Et3N),
ethanol (EtOH), ethyl acetate (EtOAc) and petroleum ether
were bought from commercial vendors. Toluene was
purchased in anhydrous form and used without further
purification. Et3N was dried over molecular sieves (3Å).
EtOH, EtOAc and petroleum ether were used as received.
Reagents as well as alkynes 1a and 1c were purchased from
commercial vendors and used as received, unless otherwise
stated. For the Sonogashira reaction, oxygen free Et3N was
obtained by bubbling argon through the solvent for 15 min.
Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm 2 E. Merck silica gel plates
(60F-254) using UV light as visualizing agent. Flash
chromatography was performed on a Biotage Isolera One
using Biotage KP-Sil columns (packed with 50μm irregular
silica) using 254 nm and 280 nm UV-light for monitoring.
NMR spectra were recorded on samples in deuterated
chloroform (CDCl3) or DMSO (DMSO-d6) on an Agilent 400
MHz (101 MHz for 13C) instrument. Residual undeuterated
chloroform (1H: δ = 7.26 ppm, 13C: δ = 77.2 ppm) or DMSO
(1H: δ = 2.50 ppm, 13C: δ = 39.5 ppm) were used as internal
reference. The following abbreviations, or a combination
thereof, were used to characterize the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad. Melting points (mp) were recorded on a Mettler FP
1-((4-Chlorophenyl)ethynyl)-3-methoxybenzene (1e).19 The
reaction was performed according to the general procedure
using 4-bromochlorobenzene (957 mg,
5
mmol),
Pd(PPh3)2Cl2 (105 mg, 0.15 mmol), CuI (28 mg, 0.15 mmol),
3-ethynylanisole (0.94 ml, 7.4 mmol) and Et3N (16 ml). Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 -> 1:0
(15 column volumes). Product 1e was obtained as a white
crystalline solid (573 mg, 47%): 1H NMR (400 MHz, CDCl3)
δ 7.47 (XX’ signal of AA’XX’ spin system, 2H), 7.33 (AA’
signal of AA’XX’ spin system, 2H), 7.29 – 7.24 (m, 1H),
7.12 (ddd, J = 7.6, 1.5, 1.0 Hz, 1H), 7.05 (ddd, J = 2.7, 1.4,
0.4 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.83 (s, 3H).
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The Journal of Organic Chemistry
13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 134.5, 133.0,
129.6, 128.8, 124.3, 124.0, 121.8, 116.5, 115.3, 90.4, 88.2,
55.5.
Product 1j was obtained as a light yellow crystalline solid
(882 mg, 81%): 1H NMR (400 MHz, DMSO-d6) δ 11.35 (br
s, 1H), 7.80 (dt, J = 1.5, 0.7 Hz, 1H), 7.58 – 7.51 (m, 2H),
7.47 – 7.35 (m, 5H), 7.27 (dd, J = 8.4, 1.6 Hz, 1H), 6.48 (ddd,
J = 2.9, 1.9, 0.9 Hz, 1H); 13C{1H} (101 MHz, DMSO-d6) δ
135.7, 131.1, 128.7, 128.1, 127.6, 126.7, 124.3, 123.9, 123.2,
112.3, 111.9, 101.4, 91.6, 86.6.
1
2
3
4
5
6
7
8
1-Methoxy-4-((4-(trifluoromethyl)phenyl)ethynyl)-benzene
(1f).20 The reaction was performed according to the general
procedure using 1-iodo-4-(trifluoromethyl)benzene (272 mg,
1 mmol), Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), CuI (5.7 mg,
0.03 mmol), 4-ethynylanisole (0.13 ml, 1.02 mmol) and Et3N
(3 ml). Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 95:5 (20 column volumes) -> 95:5 (10
column volumes). Product 1f was obtained as a white
crystalline solid (264 mg, 96%): 1H NMR (400 MHz, CDCl3)
δ 7.63 – 7.57 (m, 4H), 7.49 (XX’ signal of AA’XX’ spin
system, 2H), 6.90 (AA’ signal of AA’XX’ spin system, 2H),
3.84 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.2,
133.4, 131.7, 129.7 (q, J = 32.6 Hz), 127.6 (q, J = 1.5 Hz),
125.4 (q, J = 3.8 Hz), 124.2 (q, J = 272.1 Hz), 114.8, 114.2,
92.1, 87.0, 55.4.
3-(Phenylethynyl)thiophene (1k).25 The reaction was
performed according to the general procedure using 3-
bromothiophene (815 mg, 5 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1
mmol), CuI (19 mg, 0.1 mmol), phenylacetylene (0.6 g, 6
mmol) and Et3N (15 ml). Flash chromatography: Petroleum
ether (10 column volumes). Product 1k was obtained as a
clear oil that crystallized in matter of days (788 mg, 86%).
9
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44
45
46
47
48
49
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56
57
58
59
60
1
The compound turns orange upon air exposure: H NMR
(400 MHz, CDCl3) δ 7.57 – 7.49 (m, 3H), 7.39 – 7.32 (m,
3H), 7.31 (dd, J = 5.0, 3.0 Hz, 1H), 7.21 (dd, J = 5.0, 1.2
Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 131.7, 130.0,
128.7, 128.5, 128.4, 125.5, 123.3, 122.4, 89.0, 84.6.
4-(Phenylethynyl)aniline (1g).21 The reaction was performed
according to the general procedure using 4-iodoaniline (1.1
g, 5 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (19 mg, 0.1
mmol), phenylacetylene (0.66 ml, 6 mmol) and Et3N (15 ml).
Flash chromatography gradient: Petroleum ether/EtOAc 98:2
-> 93:7 (10 column volumes) -> 93:7 (10 column volumes)
-> 4:1 (10 column volumes). Product 1g was obtained as an
orange crystalline solid (822 mg, 85%): 1H NMR (400 MHz,
CDCl3) δ 7.52 – 7.47 (m, 2H), 7.39 – 7.28 (m, 5H), 6.65 (AA’
signal of AA’XX’ spin system, 2H), 3.82 (br s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 146.8, 133.1, 131.5, 128.4, 127.8,
124.0, 114.9, 112.8, 90.2, 87.5.
(4-Chlorophenylethynyl)ferrocene (1l).26 The reaction was
performed according to the general procedure using 4-
bromochlorobenzene (0.618 ml, 3.2 mmol), Pd(PPh3)2Cl2
(105 mg, 0.15 mmol), CuI (28 mg, 0.15 mmol),
ethynylferrocene (1.0 g, 4.8 mmol) and Et3N (16 ml). Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 ->
98:2 (10 column volumes) -> 98:2 (10 column volumes).
Product 1l was obtained as a red crystalline solid (634 mg,
1
61%): H NMR (400 MHz, CDCl3) δ 7.40 (XX’ signal of
AA’XX’ spin system, 2H), 7.30 (AA’ signal of AA’XX’ spin
system, 2H), 4.51 – 4.49 (m, 2H), 4.26 – 4.24(m, 7H);
13C{1H} NMR (101 MHz, CDCl3) δ 133.7, 132.7, 128.7,
122.6, 89.6, 84.8, 71.6, 70.2, 69.2, 65.1.
2-(Phenylethynyl)aniline (1h).22 The reaction was performed
according to the general procedure using 2-iodoaniline (1.1
g, 5 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (19 mg, 0.1
mmol), phenylacetylene (0.66 ml, 6 mmol) and Et3N (15 ml).
Flash chromatography gradient: Petroleum ether/EtOAc 1:0
-> 1:0 (5 column volumes) -> 85:15 (15 column volumes).
Product 1h was obtained as a yellow crystalline solid (769
Benzyl 4-(phenylethynyl)benzoate (1m). This compound was
prepared in two steps via the corresponding methyl ester.
Step
1
–
Sonogashira
reaction:
Methyl
4-
(phenylethynyl)benzoate27 was first prepared according to
the general procedure using methyl 4-iodoacetophenone
(1.23 g, 5 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (19
mg, 0.1 mmol), phenylacetylene (0.61 g, 6 mmol) and Et3N
(15 ml). Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 1:0 (10 column volumes) -> 95:5 (10
column volumes) -> 9:1 (5 column volumes) -> 9:1 (15
column volumes). Product was obtained as a light yellow
crystalline solid (689 mg, 58%): 1H NMR (400 MHz, CDCl3)
δ 8.03 (XX’ signal of AA’XX’ spin system, 2H), 7.59 (AA’
signal of AA’XX’ spin system, 2H), 7.57 – 7.52 (m, 2H),
7.40 – 7.34 (m, 3H), 3.93 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 166.7, 131.9, 131.6, 129.64, 129.59, 128.9, 128.6,
128.1, 122.8, 92.5, 88.8, 52.4. Step 2 – transesterification: A
1
mg, 80%): H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m,
2H), 7.40 – 7.32 (m, 4H), 7.14 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H),
6.75 – 6.70 (m, 2H), 4.28 (br s, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 147.9, 132.2, 131.6, 129.8, 128.5, 128.3,
123.4, 118.1, 114.4, 108.0, 94.8, 86.0.
3-(Phenylethynyl)pyridine (1i).23 The reaction was
performed according to the general procedure using 3-
bromopyridine (0.48 ml, 5 mmol), Pd(PPh3)2Cl2 (105 mg,
0.15 mmol), CuI (28 mg, 0.15 mmol), phenylacetylene (0.81
ml, 7.4 mmol) and Et3N (16 ml). Flash chromatography
gradient: Petroleum ether/EtOAc 1:0 -> 9:1 (10 column
volumes) -> 9:1 (15 column volumes). Product 1i was
obtained as a light brown crystalline solid (546 mg, 61%): 1H
NMR (400 MHz, CDCl3) δ 8.77 (dd, J = 2.2, 0.9 Hz, 1H),
8.55 (dd, J = 4.9, 1.7 Hz, 1H), 7.81 (ddd, J = 7.9, 2.2, 1.7 Hz,
1H), 7.59 – 7.52 (m, 2H), 7.40 – 7.35 (m, 3H), 7.29 (ddd, J =
7.9, 4.9, 0.9 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
152.4, 148.7, 138.6, 131.8, 129.0, 128.6, 123.2, 122.7, 120.6,
92.8, 86.1.
5-(Phenylethynyl)-1H-indole (1j).24 The reaction was
performed according to the general procedure using 5-
iodoindole (1.22 g, 5 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1
mmol), CuI (19 mg, 0.1 mmol), phenylacetylene (0.6 g, 6
mmol) and Et3N (15 ml). Flash chromatography gradient:
Petroleum ether/EtOAc 1:0 -> 1:0 (10 column volumes) ->
9:1 (20 column volumes) -> 9:1 (20 column volumes).
dry
5
ml reaction vial containing methyl 4-
(phenylethynyl)benzoate (71 mg, 0.3 mmol), tBuOK (17 mg,
0.15 mmol), benzyl alcohol (0.31 ml, 3 mmol) and toluene
(0.7 ml) was heated in a Radleys HeatOn™ block to 100 °C
for 24 h under an atmosphere of argon. The reaction was
cooled to room temperature and the toluene was evaporated
under a stream of N2. The resulting mixture was taken up in
~0.5 ml DCM and transferred to a 1g Biotage KP-Sil samplet.
After allowing the samplet to dry it was transferred to a 10 g
column and purified through flash chromatography.
Gradient: Petroleum ether/EtOAc 1:0 -> 1:0 (5 column
volumes) -> 9:1 (25 column volumes). Product 1m was
obtained as a white crystalline solid: mp = 103 – 105°C;
νmax/cm-1 3031 (C-H), 2958 (C-H), 2213 (C≡C), 1709 (C=O),
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Page 8 of 13
1604 (C=C);1H NMR (400 MHz, CDCl3) δ 8.07 (XX’ signal
(101 MHz, CDCl3) δ 137.5, 128.8 (2 signals overlap), 127.8,
126.6.
1
2
3
4
5
6
7
8
of AA’XX’ spin system, 2H), 7.59 (AA’ signal of AA’XX’
spin system, 2H), 7.57 – 7.53 (m, 2H), 7.49 – 7.45 (m, 2H),
7.44 – 7.34 (m, 6H), 5.38 (s, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 166.0, 136.0, 131.9, 131.6, 129.8, 129.6, 128.9,
128.8, 128.6, 128.5, 128.4, 128.3, 122.8, 92.6, 88.8, 67.0;
HRMS (ESI+ QTOF) calculated for C22H17O2 [M + H]+
313.1223, found 313.1221.
1-(4-(Phenylethynyl)phenyl)ethan-1-one (1n).28 The reaction
was performed according to the general procedure using
methyl 4-iodobenzoate (1.3 g, 5 mmol), Pd(PPh3)2Cl2 (105
mg, 0.15 mmol), CuI (28 mg, 0.15 mmol), phenylacetylene
(0.81 g, 7.4 mmol) and Et3N (16 ml). Flash chromatography
gradient: Petroleum ether/EtOAc 1:0 -> 1:0 (5 column
volumes) -> 99:1 (3 column volumes) -> 9:1 (11 column
volumes). Product 1n was obtained as an off-white
crystalline solid (337 mg, 31%): 1H NMR (400 MHz, CDCl3)
δ 7.93 (XX’ signal of AA’XX’ spin system, 2H), 7.61 (AA’
signal of AA’XX’ spin system, 2H), 7.58 – 7.52 (m, 2H),
7.41 – 7.34 (m, 3H), 2.60 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 197.4, 136.3, 131.8, 131.8, 128.9, 128.6, 128.4,
128.3, 122.7, 92.8, 88.7, 26.7.
(E)-1-Methoxy-4-styrylbenzene (2b).6 The reaction was
performed according to Method A using 1-methoxy-4-
(phenylethynyl)benzene (187 mg, 0.90 mmol), Ru3(CO)12
(3.8 mg, 0.006 mmol), tBuOK (20 mg, 0.18 mmol), benzyl
alcohol (0.93 ml, 9.0 mmol) and toluene (2.1 ml) with a
reaction time of 44 h. NMR-yield (E/Z %): 100/0. Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 ->
95:5 (20 column volumes) -> 95:5 (10 column volumes).
Product 2b was obtained as an off white crystalline solid
which was contaminated with 11 % benzyl benzoate (198 mg
total, 177 mg only considering product, 93%). An
analytically pure sample could be obtained through
recrystallization from EtOH: 1H NMR (400 MHz, CDCl3) δ
7.54 – 7.49 (m, 2H), 7.47 (XX’ signal of AA’XX’ spin
system, 2H), 7.36 (dd, J = 8.4, 6.9 Hz, 2H), 7.28 – 7.23 (m,
1H), 7.09 (d, J = 16.3 Hz, 1H), 6.99 (d, J = 16.3 Hz, 1H), 6.92
(AA’ signal of AA’XX’ spin system, 2H), 3.84 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 159.4, 137.8, 130.3,
128.8, 128.3, 127.9, 127.3, 126.7, 126.4, 114.3, 55.5.
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-1-Chloro-4-styrylbenzene (2c).10j The reaction was
performed according to Method A using 1-chloro-4-
(phenylethynyl)benzene (128 mg, 0.60 mmol), Ru3(CO)12
(2.6 mg, 0.004 mmol), tBuOK (14 mg, 0.12 mmol), benzyl
alcohol (0.62 ml, 6.0 mmol) and toluene (1.4 ml) with a
reaction time of 42 h. NMR-yield (E/Z %): 100/0. Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 ->
95:5 (10 column volumes) -> 95:5 (10 column volumes).
Product 2c was obtained as a white crystalline solid (109 mg,
Semi-hydrogenation of internal alkynes, Method A: To an
oven-dried 5 ml Biotage microwave reaction vial equipped
with a magnetic stirring bar was transferred alkyne,
Ru3(CO)12 and tBuOK (see each compound for amounts).
The vial was sealed with a Biotage cap and connected to a
Schlenk-line. The atmosphere was evacuated and the vial was
refilled with argon (3 cycles). Dry toluene and benzyl alcohol
were subsequently transferred (no special precautions were
taken to exclude air from these components). The Schlenk-
connection was removed and the sealed system was heated in
a Radleys HeatOn™ block to 100 °C. After being stirred at
that temperature for an indicated period of time, the reaction
was allowed to cool to room temperature and toluene was
removed under a stream of N2. The reported NMR-yields
were obtained using 2,5-dimethylfuran as internal standard.29
Everything was taken up in ~2 ml CDCl3 and a 1H-NMR was
recorded (no of transients: 2, relaxation delay: 60s). The
spectrum was phase corrected and baseline corrected before
being integrated. The amount of product was calculated as
previously described using the 2,5-dimethylfuran HAr peak at
δ 5.87 ppm and appropriate product peaks. As an example,
the hydrogenation of phenylacetylene with cyclopentanol as
hydrogen donor can be found in the SI (Fig. S1). The CDCl3
was after analysis evaporated and the crude mixture was
taken up in ~1-3 ml DCM and transferred to either a 1 g or 3
g Biotage KP-Sil samplet. After drying the samplet was
transferred to a 10 g or a 25 g column and purified through
flash chromatography.
1
85 %): H NMR (400 MHz, CDCl3) δ 7.55 – 7.49 (m, 2H),
7.45 (XX’ signal of AA’XX’ spin system, 2H), 7.42 – 7.36
(m, 2H), 7.34 (AA’ signal of AA’XX’ spin system, 2H), 7.32
– 7.27 (m, 1H), 7.10 (d, J = 16.4, 1H), 7.05 (d, J = 16.4, 1H);
13C NMR (101 MHz, CDCl3) δ 137.1, 136.0, 133.3, 129.4,
129.0, 128.9, 128.0, 127.8, 127.5, 126.7.
(E)-1-Styryl-4-(trifluoromethyl)benzene (2d).31 The reaction
was performed according to Method A using 1-(2-
phenylethynyl)-4-(trifluoromethyl)benzene (195 mg, 0.79
mmol), Ru3(CO)12 (3.4 mg, 0.005 mmol), tBuOK (18 mg,
0.16 mmol), benzyl alcohol (0.82 ml, 7.9 mmol) and toluene
(1.8 ml) with a reaction time of 24 h. NMR-yield (E/Z %):
~100/0 (product peaks overlap with benzyl alcohol,
rendering
exact
measurement
difficult).
Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 -> 1:0
(5 column volumes) -> 99:1 (5 column volumes). Product 2d
was obtained as a white crystalline solid (175 mg, 89 %): 1H
NMR (400 MHz, CDCl3) δ 7.66 – 7.59 (m, 4H), 7.58 – 7.54
(m, 2H), 7.44 – 7.39 (m, 2H), 7.37 – 7.31 (m, 1H), 7.22 (d, J
= 16.3 Hz, 1H), 7.13 (d, J = 16.3 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 140.8 (q, J = 1.5 Hz), 136.6, 131.2,
129.2 (q, J = 32.4 Hz), 128.8, 128.3, 127.1 (q, J = 0.8 Hz),
126.8, 126.6, 125.6 (q, J = 3.8 Hz), 124.3 (q, J = 272 Hz).
Method B: As for Method A but using RuCl2(DMSO)4 (10
mol%) as the catalyst, iPrOH (10 equivalents) as the
hydrogen donor, and 50 mol% tBuOK as the base.
(E)-Stilbene ((E)-2a).30 The reaction was performed
according to Method A using diphenylacetylene (107 mg,
0.60 mmol), Ru3(CO)12 (2.6 mg, 0.004 mmol), tBuOK (14
mg, 0.12 mmol), benzyl alcohol (0.62 ml, 6.0 mmol) and
toluene (1.4 ml) with a reaction time of 24 h. NMR-yield (E/Z
%): 100/0. Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 1:0 (10 column volumes). Product (E)-2a
(E)-1-(4-Chlorostyryl)-3-methoxybenzene
(2e).32
The
reaction was performed according to Method A using 1-
chloro-4-[2-(3-methoxyphenyl)ethynyl]benzene (218 mg,
0.9 mmol), Ru3(CO)12 (3.8 mg, 0.006 mmol), tBuOK (20 mg,
0.18 mmol), benzyl alcohol (0.93 ml, 9.0 mmol) and toluene
(2.1 ml) with a reaction time of 24 h. NMR-yield (E/Z %):
100/0. Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 97:3 (20 column volumes) -> 97:3 (10
column volumes). Product 2e was obtained as a white
crystalline solid (191 mg, 87%): mp = 71°C; νmax/cm-1 3006
1
was obtained as a white crystalline solid (95 mg, 88 %): H
NMR (400 MHz, CDCl3) δ 7.57 – 7.51 (m, 4H), 7.42 – 7.35
(m, 6H), 7.31 – 7.25 (m, 1H), 7.12 (s, 2H); 13C{1H} NMR
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(C-H), 2835 (C-H), 1605 (C=C); 1H NMR (400 MHz, CDCl3)
δ 7.48 – 7.42 (XX’ signal of AA’XX’ spin system, 2H), 7.34
– 7.31 (AA’ signal of AA’XX’ spin system, 2H), 7.31 – 7.26
(m, 1H), 7.10 (ddd, J = 7.7, 1.6, 0.9 Hz, 1H), 7.05 (s, 2H),
7.04 (dd, J = 2.5, 1.5 Hz, 1H), 6.84 (ddd, J = 8.2, 2.6, 0.9 Hz,
1H), 3.85 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.0,
138.6, 135.9, 133.4, 129.8, 129.3, 129.0, 127.8, 127.8, 119.4,
113.6, 111.9, 55.4; HRMS (ESI+ QTOF) calculated for
C15H14ClO [M + H]+ 245.0728, found 245.0730.
time of 70 h. NMR-yield (E/Z %): 70/30. The crude product
was transferred to an amino-functionalized 1 g samplet
instead of the unfunctionalized samplet described in general
procedure 2. Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 85:15 (15 column volumes) -> 85:15 (10
column volumes). Product 2i was obtained as a light yellow
crystalline solid (26 mg, 48%): 1H NMR (400 MHz, CDCl3)
δ 8.72 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.83
(dddd, J = 8.0, 2.2, 1.6, 0.6 Hz, 1H), 7.56 – 7.50 (m, 2H),
7.41 – 7.35 (m, 2H), 7.33 – 7.26 (m, 2H), 7.17 (d, J = 16.4
Hz, 1H), 7.07 (d, J = 16.4 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 148.6, 136.7, 133.1, 132.8, 130.9, 128.9, 128.3,
126.8, 125.0, 123.7.
1
2
3
4
5
6
7
8
(E)-1-Methoxy-4-(4-(trifluoromethyl)styryl)benzene (2f).10j
The reaction was performed according to Method A using 1-
methoxy-4-((4-(trifluoromethyl)phenyl)ethynyl)-benzene
(83 mg, 0.3 mmol), Ru3(CO)12 (1.3 mg, 0.002 mmol), tBuOK
(7 mg, 0.06 mmol), benzyl alcohol (0.31 ml, 3.0 mmol) and
toluene (0.69 ml) with a reaction time of 42 h. NMR-yield
(E/Z %): 100/0. Flash chromatography gradient: Petroleum
ether/EtOAc 1:0 -> 1:0 (10 column volumes) -> 95:5 (10
column volumes). Product 2f was obtained as a white
crystalline solid contaminated with a small amount of benzyl
benzoate (69 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.63
– 7.55 (m, 4H), 7.48 (XX’ signal of AA’XX’ spin system,
2H), 7.15 (d, J = 16.3 Hz, 1H), 6.98 (d, J = 16.3 Hz, 1H), 6.93
(AA’ signal of AA’XX’ spin system, 2H), 3.84 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 159.9, 141.1, 130.7,
129.4, 128.8 (q, J = 32.4 Hz), 128.1, 126.3, 125.6 (q, J = 3.9
Hz), 124.9, 124.3 (q, J = 271 Hz), 114.2, 55.3.
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15
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17
18
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-5-Styryl-1H-indole (2j).36 The reaction was performed
according to Method B using 5-(phenylethynyl)-1H-indole
(131 mg, 0.6 mmol), RuCl2(DMSO)4 (29 mg, 0.06 mmol),
tBuOK (34 mg, 0.3 mmol), 2-propanol (0.46 ml, 6.0 mmol)
and toluene (1.54 ml) with a reaction time of 72 h. NMR-
yield: 75%. Flash chromatography gradient: Petroleum
ether/EtOAc 96:4 -> 92:8 (10 column volumes) -> 92:8 (8
column volumes). Product 2j was obtained as an off white
crystalline solid (74 mg, 56%): 1H NMR (400 MHz, CDCl3)
δ 8.15 (br s, 1H), 7.77 (dt, J = 1.6, 0.8 Hz, 1H), 7.56 – 7.52
(m, 2H), 7.46 (dd, J = 8.5, 1.7 Hz, 1H), 7.41 – 7.34 (m, 3H),
7.25 (d, J = 16.3 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.21 (dd, J =
3.3, 2.3 Hz, 1H), 7.09 (d, J = 16.3 Hz, 1H), 6.57 (ddd, J =
3.1, 2.0, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
138.1, 135.7, 130.2, 129.6, 128.8, 128.3, 127.1, 126.3, 126.2,
124.9, 120.8, 119.6, 111.4, 103.1.
(E)-4-Styrylaniline (2g).33 The reaction was performed
according to Method B using 4-(phenylethynyl)aniline (58
mg, 0.3 mmol), RuCl2(DMSO)4 (14.5 mg, 0.03 mmol),
tBuOK (17 mg, 0.15 mmol), 2-propanol (0.23 ml, 3.0 mmol)
and toluene (0.77 ml) with a reaction time of 24 h. NMR-
yield (E/Z %): 65/14. Flash chromatography gradient:
Petroleum ether/EtOAc 95:5 -> 85:15 (30 column volumes).
Product 2g was obtained as a light yellow crystalline solid
(30 mg, 51%): 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.45 (m,
2H), 7.39 – 7.29 (m, 4H), 7.25 – 7.18 (m, 1H), 7.03 (d, J =
16.3 Hz, 1H), 6.93 (d, J = 16.3 Hz, 1H), 6.67 (AA’ signal of
AA’XX’ spin system, 2H), 3.75 (br s, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 146.3, 138.1, 128.8, 128.7, 128.2,
127.9, 127.0, 126.2, 125.2, 115.3.
(E)-2-Styrylaniline (2h).34 The reaction was performed
according to Method A using 2-(2-phenylethynyl)aniline
(174 mg, 0.90 mmol), Ru3(CO)12 (19 mg, 0.03 mmol),
tBuOK (20 mg, 0.18 mmol), benzyl alcohol (0.93 ml, 9.0
mmol) and toluene (2.1 ml) with a reaction time of 28 h.
NMR-yield (E/Z %): 45/14. Flash chromatography gradient:
Petroleum ether/EtOAc 98:2 -> 9:1 (30 column volumes).
Product 2h was obtained as a white crystalline solid that
rapidly turned brown upon air exposure (60 mg, 34%). A
sample was obtained for analytical purposes through
recrystallization from EtOH: 1H NMR (400 MHz, CDCl3) δ
7.57 – 7.52 (m, 2H), 7.44 (dd, J = 7.7, 1.5 Hz, 1H), 7.43 –
7.37 (m, 2H), 7.33 – 7.27 (m, 1H), 7.20 (d, J = 16.1 Hz, 1H),
7.17 – 7.12 (m, 1H), 7.02 (d, J = 16.1 Hz, 1H), 6.89 – 6.82
(m, 1H), 6.74 (dd, J = 8.0, 1.2 Hz, 1H), 3.82 (br s, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 144.1, 137.7, 130.4,
128.80, 128.78, 127.7, 127.4, 126.5, 124.4, 123.9, 119.7,
116.4.
(E)-3-Styrylthiophene (2k).37 The reaction was performed
according to Method A using 3-(phenylethynyl)thiophene
(166 mg, 0.90 mmol), Ru3(CO)12 (3.8 mg, 0.006 mmol),
tBuOK (20 mg, 0.18 mmol), benzyl alcohol (0.93 ml, 9.0
mmol) and toluene (2.1 ml) with a reaction time of 48 h.
NMR-yield (E/Z %): 89/10. Flash chromatography:
Petroleum ether (10 column volumes). Product 2k was
obtained as a white crystalline solid which was contaminated
1
with 3% (Z)-3-styrylthiophene (127 mg, 76%): H NMR
(400 MHz, CDCl3) δ 7.53 – 7.48 (m, 2H), 7.41 – 7.31 (m,
4H), 7.30 – 7.25 (m, 2H), 7.15 (d, J = 16.3 Hz, 1H), 6.98
(d, J = 16.3 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
140.2, 137.5, 128.79, 128.78, 127.6, 126.4, 126.3, 125.0,
123.0, 122.5.
(E)-(4-Chlorophenyl)ferrocenylethene (2l). The reaction was
performed according to Method A using 1-chloro-4-
(ferroceneethynyl)benzene (192 mg, 0.60 mmol), Ru3(CO)12
(2.6 mg, 0.004 mmol), tBuOK (14 mg, 0.12 mmol), benzyl
alcohol (0.62 ml, 6.0 mmol) and toluene (1.4 ml) with a
reaction time of 24 h. NMR-yield (E/Z %): 60/n.d. Flash
chromatography gradient: Petroleum ether/EtOAc 1:0 -> 1:0
(10 column volumes) -> 97:3 (10 column volumes). Product
2l was obtained as a red crystalline solid (95 mg, 49%): mp
= 154 – 158°C; νmax/cm-1 3083 (C-H), 2956 (C-H), 2924 (C-
H), 2854 (C-H), 1632 (C=C); 1H NMR (400 MHz, CDCl3) δ
7.34 (XX’ signal of AA’XX’ spin system, 2H), 7.29 (AA’
signal of AA’XX’ spin system, 2H), 6.85 (d, J = 16.1 Hz,
1H), 6.64 (d, J = 16.1 Hz, 1H), 4.47 – 4.45 (t, J = 1.9 Hz, 2H),
4.29 (t, J = 1.8 Hz, 2H), 4.14 (s, 5H); 13C{1H} NMR (101
MHz, CDCl3) δ 136.5, 132.3, 128.9, 127.9, 127.0, 124.8,
83.0, 69.7, 69.3, 67.1; HRMS (ESI+ QTOF) calculated for
C18H16ClFe [M + H]+ 323.0284, found 323.0268.
(E)-3-Styrylpyridine (2i).35 The reaction was performed
according to general procedure
2
using 3-(2-
phenylethynyl)pyridine (54 mg, 0.30 mmol), Ru3(CO)12 (6.3
mg, 0.01 mmol), tBuOK (6.7 mg, 0.06 mmol), benzyl alcohol
(0.31 ml, 3.0 mmol) and toluene (0.69 ml) with a reaction
Benzyl (E)-4-styrylbenzoate (2m). The reaction was
performed according to Method A using benzyl 4-
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(phenylethynyl)benzoate (84 mg, 0.27 mmol), Ru3(CO)12
2927 (C-H), 1681 (C=O), 1602 (C=C); 1H NMR (400 MHz,
1
2
3
4
5
6
7
8
(1.2 mg, 0.0018 mmol), tBuOK (6.1 mg, 0.054 mmol),
benzyl alcohol (0.28 ml, 0.27 mmol) and toluene (0.65 ml)
with a reaction time of 24 h. NMR-yield (E/Z %): 100/0.
Flash chromatography gradient: Petroleum ether/EtOAc 1:0
-> 1:0 (5 column volumes) -> 9:1 (20 column volumes).
Product 2m was obtained as a white crystalline solid (60 mg,
71%): mp = 123 – 129°C; νmax/cm-1 3027 (C-H), 2952 (C-H),
) δ 7.96 (XX’ signal of AA’XX’ spin system, 2H), 7.58 (AA’
signal of AA’XX’ spin system, 2H), 7.56 – 7.52 (m, 2H),
7.42 – 7.36 (m, 2H), 7.35 – 7.27 (m, 4H), 7.26 – 7.20 (m,
1H), 7.23 (d, J = 16.4 Hz, 1H). 7.13 (d, J = 16.3 Hz, 1H), 3.35
– 3.28 (m, 2H), 3.09 (dd, J = 8.5, 6.9 Hz, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 198.7, 142.1, 141.5, 136.8, 135.8,
131.6, 128.9, 128.7, 128.7, 128.6, 128.4, 127.6, 126.9, 126.7,
126.3, 40.6, 30.4; HRMS (ESI+ QTOF) calculated for
C23H21O [M + H]+ 313.1592, found 313.1592.
1
2892 (C-H), 1708 (C=O), 1603 (C=C); H NMR (400 MHz,
CDCl3) δ 8.10 – 8.05 (m, 2H), 7.60 – 7.52 (m, 4H), 7.50 –
7.45 (m, 2H), 7.44 – 7.34 (m, 5H), 7.33 – 7.28 (m, 1H), 7.22
(d, J = 16.3 Hz, 1H), 7.13 (d, J = 16.4 Hz, 1H), 5.38 (s, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 142.1, 136.8,
136.2, 131.4, 130.3, 129.0, 128.9, 128.7, 128.4, 128.4, 128.3,
127.7, 126.9, 126.5, 66.8; HRMS (ESI+ QTOF) calculated
for C22H19O2 [M + H]+ 315.1380, found 315.1378.
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ASSOCIATED CONTENT
1H and 13C{1H} NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(E)-1-(4-Styrylphenyl)ethan-1-ol (2n). The reaction was
Corresponding Author
performed according to Method
B
using 1-(4-
*kann@chalmers.se
(phenylethynyl)phenyl)ethan-1-one (66 mg, 0.3 mmol),
RuCl2(DMSO)4 (29 mg, 0.006 mmol), tBuOK (17 mg, 0.15
mmol), 2-propanol (0.23 ml, 3.0 mmol) and toluene (0.77 ml)
with a reaction time of 70 h. NMR-yield (E/Z %): 52/0. Flash
chromatography gradient: Petroleum ether/EtOAc 100:0 ->
85:15 (20 column volumes) -> 85:15 (10 column volumes).
Product 2n was obtained as a white crystalline solid (29 mg,
44%): mp = 118 – 120°C; νmax/cm-1 3307 (O-H), 3024 (C-H),
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The Swedish Research Council Formas (N.K., grant no 942-2015-
1106) and the Swedish Research Council (N.K, grant no 2015-
06350) are gratefully acknowledged for funding.
1
2973 (C-H); H NMR (400 MHz, CDCl3) δ 7.56 – 7.48 (m,
4H), 7.41 – 7.33 (m, 4H), 7.29 – 7.24 (m, 1H), 7.11 (s, 2H),
4.92 (qd, J = 6.4, 2.9 Hz, 1H), 1.81 (d, J = 2.5 Hz, 1H), 1.52
(d, J = 6.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
145.3, 137.4, 136.8, 128.8, 128.8, 128.4, 127.8, 126.8, 126.6,
125.9, 70.4, 25.3; HRMS (ESI+ QTOF) calculated for
C16H15 [M+H-[H2O]]+ 207.1168, found 207.1178.
REFERENCES
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Essential Oils and Their Single Compounds in Cosmetics—a Critical
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4. Srimani, D.; Diskin-Posner, Y.; Ben-David, Y.; Milstein, D., Iron
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Tandem semi-hydrogenation/hydrogen borrowing.
(E)-N-Benzyl-4-styrylaniline (4).38 The reaction was
performed according to Method
A
using 4-
(phenylethynyl)aniline (39 mg, 0.2 mmol), Ru3(CO)12 (4.2
mg, 0.007 mmol), tBuOK (4.5 mg, 0.04 mmol), benzyl
alcohol (0.21 ml, 2.0 mmol) and toluene (0.46 ml) with a
reaction time of 24 h. NMR-yield (4-[(E)-styryl]aniline/ N-
benzyl-4-[(E)-styryl]aniline
%):
23/51.
Flash
chromatography gradient: Petroleum ether/EtOAc 98:2 ->
9:1 (30 column volumes). Product 4 was obtained as an off-
1
white crystalline solid (17 mg, 30%): H NMR (400 MHz,
CDCl3) δ 7.51 – 7.46 (m, 2H), 7.41 – 7.28 (m, 9H), 7.24 –
7.19 (tt, J = 1.3, 7.3 Hz, 1H), 7.04 (d, J = 16.3 Hz, 1H), 6.92
(d, J = 16.3 Hz, 1H), 6.65 (AA’ signal of AA’XX’ spin
system, 2H), 4.38 (s, 2H), 4.20 (br s, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 147.9, 139.3, 138.2, 128.9, 128.8, 128.7,
127.9, 127.6, 127.5, 127.2, 126.9, 126.2, 124.7, 113.1, 48.3.
(E)-3-phenyl-1-(4-styrylphenyl)propan-1-one (6). The
reaction was performed according to Method A using 1-(4-
(phenylethynyl)phenyl)ethan-1-one (66 mg, 0.3 mmol),
Ru3(CO)12 (1.3 mg, 0.002 mmol), tBuOK (6.7 mg, 0.06
mmol), benzyl alcohol (0.31 ml, 3.0 mmol) and toluene (0.69
ml) with a reaction time of 24 h. NMR-yield: 45%. Flash
chromatography gradient: Petroleum ether/EtOAc 100:0 ->
100:0 (5 column volumes) -> 80:20 (25 column volumes). A
mixture of product 6 and benzyl alcohol was obtained after
chromatography. The mixture was recrystallized from
boiling EtOAc, yielding pure 6 as white crystals. The mother
liquid was recrystallized again yielding another batch of pure
6 (33 mg, 35%): mp = 150 – 155°C; νmax/cm-1 3026 (C-H),
6. Richmond, E.; Moran, J., Ligand Control of E/Z Selectivity in
Nickel-Catalyzed Transfer Hydrogenative Alkyne Semireduction. J.
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7. Zhao, C. Q.; Chen, Y. G.; Qiu, H.; Wei, L.; Fang, P.; Mei, T. S.,
Water as a Hydrogenating Agent: Stereodivergent Pd-Catalyzed
Semihydrogenation of Alkynes. Org. Lett. 2019, 21, 1412-1416.
8. Zhou, Y. P.; Mo, Z. B.; Luecke, M. P.; Driess, M., Stereoselective
Transfer Semi-Hydrogenation of Alkynes to E-Olefins with N-
Heterocyclic Silylene-Manganese Catalysts. Chem. Eur. J. 2018, 24,
4780-4784.
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Directed Resveratrol Derivatives for the Treatment of Alzheimer's
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Sun, F., Ligand-Controlled Iridium-Catalyzed Semihydrogenation of
Alkynes with Ethanol: Highly Stereoselective Synthesis of E- and Z-
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Detection to Enable Selective Alkyne trans-Hydrogenation with
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Saruwatari, S.; Isono, A.; Takada, Y.; Nishimori, R.; Tsujiwaki, M.;
Sakaue, N.; Matsuzaka, H., Bis(Bipyridine) Ruthenium(II)
Bis(Phosphido) Metalloligand: Synthesis of Heterometallic Complexes
and Application to Catalytic (E)-Selective Alkyne Semi-
Hydrogenation. Dalton Trans. 2019, 48, 1161-1165.
1
2
3
4
5
6
7
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17. Park, S. B.; Alper, H., Recyclable Sonogashira Coupling
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M., Entangled Palladium Nanoparticles in Resin Plugs. Chem.
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19. Wang, S.; Min, Y. S.; Zhang, X. W.; Xi, C. J., External Oxidant-
Free Cross-Coupling of Arylcopper and Alkynylcopper Reagents
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and High Yielding Synthesis of Symmetrical and Unsymmetrical
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1,3,5,7-Tetramethyl-2,4,8-Trioxa-6-Phenyl-6-Phosphaadamantane:
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69, 5082-5086.
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Prastaro, A.; Niembro, S.; Shafir, A.; Vallribera, A., Perfluoro-Tagged,
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9
10. (a) Blum, Y.; Reshef, D.; Shvo, Y., H-Transfer Catalysis with
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Parkhomenko, K.; Hijazi, A.; Chemmi, A.; Allouche, L.; Brelot, L.;
Pfeffer, M.; Ricard, L.; Le Goff, X. F., Mu-Chlorido, Mu-Hydroxo-
Bridged Dicarbonyl Ruthenacycles: Synthesis, Structure and Catalytic
Properties in Hydrogen Atom Transfer. Dalton Trans. 2009, 2695-
2711; (c) Li, J.; Hua, R. M., Stereodivergent Ruthenium-Catalyzed
Transfer Semihydrogenation of Diaryl Alkynes. Chem. Eur. J. 2011,
17, 8462-8465; (d) Radkowski, K.; Sundararaju, B.; Furstner, A., A
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