Dehydrogenative alcohol coupling and one-pot cross metathesis/dehydrogenative coupling reactions of alcohols using Hoveyda-Grubbs catalysts

Article abstract of DOI:10.1039/d1nj00255d

In this study,in situformed ruthenium hydride species that were generated from Grubbs type catalysts are used as efficient catalysts for dehydrogenative alcohol coupling and sequential cross-metathesis/dehydrogenative coupling reactions. The selectivity of Grubbs first generation catalysts (G1) in dehydrogenative alcohol coupling reactions can be tuned for the ester formation in the presence of weak bases, while the selectivity can be switched to the β-alkylated alcohol formation using strong bases. The performance of Hoveyda-Grubbs 2nd generation catalyst (HG2) was improved in the presence of tricyclohexylphosphine for the selective synthesis of ester derivatives with weak and strong bases in quantitative yields. Allyl alcohol was used as self and cross-metathesis substrate for the HG2 catalyzed sequential cross-metathesis/dehydrogenative alcohol coupling reactions to obtain γ-butyrolactone and long-chain ester derivatives in quantitative yields.

Full text of DOI:10.1039/d1nj00255d

NJC
View Article Online
View Journal | View Issue
PAPER
Dehydrogenative alcohol coupling and one-pot
cross metathesis/dehydrogenative coupling
reactions of alcohols using Hoveyda–Grubbs
catalysts†
Cite this: New J. Chem., 2021,
4
5, 5992
Halenur O¨ zer, Dilan Arslan and Bengi O¨ zgun O¨ zturk
*
¨
¨
In this study, in situ formed ruthenium hydride species that were generated from Grubbs type catalysts
are used as efficient catalysts for dehydrogenative alcohol coupling and sequential cross-metathesis/
dehydrogenative coupling reactions. The selectivity of Grubbs first generation catalysts (G1) in
dehydrogenative alcohol coupling reactions can be tuned for the ester formation in the presence of
weak bases, while the selectivity can be switched to the b-alkylated alcohol formation using strong
bases. The performance of Hoveyda–Grubbs 2nd generation catalyst (HG2) was improved in the
presence of tricyclohexylphosphine for the selective synthesis of ester derivatives with weak and
strong bases in quantitative yields. Allyl alcohol was used as self and cross-metathesis substrate for
the HG2 catalyzed sequential cross-metathesis/dehydrogenative alcohol coupling reactions to obtain
g-butyrolactone and long-chain ester derivatives in quantitative yields.
Received 15th January 2021,
Accepted 9th March 2021
DOI: 10.1039/d1nj00255d
rsc.li/njc
self-coupling of secondary alcohols to yield racemic ketones
through dehydrogenative Guerbet reactions. In 2017, protic
Introduction
1
7
Alcohols are important building blocks for synthetic organic NHC ruthenium complexes were used in dehydrogenative alcohol
and pharmaceutical chemistry to build advanced organic coupling reactions of secondary alcohols and coupling of primary
1
,2
18
structures.
The transformation of commercially available and secondary alcohols to yield functional ketone derivatives.
alcohol derivatives to functional compounds using transition Ruthenium hydride complexes bearing unsymmetrical tridentate
metal-based catalysts have been intensively studied over the (NNN) ligands were used as alternative catalysts for the coupling
3
–5
last decade.
reaction is one of the most important processes for the synthesis reactions. In addition to specially designed ruthenium catalysts,
of carboxylic acids, ketones, esters, lactones and substituted commercially available RuCl (PPh performed the dehydrogena-
mono-alcohol derivatives in an efficient manner. Several transi- tive coupling reactions of primary alcohols to give Guerbet alcohol
Acceptorless dehydrogenative alcohol coupling of primary and secondary alcohols through b-alkylation
19
2
3 3
)
20
tion metal catalysts based on cobalt, manganese, iridium, ruthe- derivatives in the presence of potassium-tert-butoxide. As can be
nium are mostly used in dehydrogenative alcohol coupling seen from literature examples, dehydrogenative coupling reac-
6
–12
reactions.
Among these transition based metal catalysts, tions can be manipulated through the selection of suitable
ruthenium is the most frequently used catalyst in dehydrogena- catalysts and reaction conditions for the selective formation of
tive alcohol coupling reactions. Verpoort, Madsen and M ¨o ller ester and Guerbet alcohols.
have utilized different N-heterocyclic carbene/ruthenium-arene
As an important alcohol-transformation reaction, cross-
complexes to build carboxylic acids through dehydrogenative metathesis of unsaturated alcohols that are catalyzed by well-
alcohol coupling reactions of primary alcohols in the presence of defined metathesis catalysts can be used for the formation of
1
3–15
21–24
strong bases such as KOH and NaOH.
used RuCl (IPr)(p-cymene) for acceptorless dehydrogenative Unsaturated alcohols are considered as challenging substrates
alcohol coupling reactions of primary alcohols to obtain func- for cross-metathesis reactions owing to their ability to form
In 2011, Madsen et al. unsaturated functional molecules in a highly efficient way.
2
1
6
tional ester derivatives. Later on, Madsen et al. reported the ruthenium hydride species in the presence of Grubbs catalyst,
2
5
which triggers the undesired olefin isomerization reactions. In
020, tandem cross-metathesis/hydrogenation reactions of allyl
alcohol with 1-octene in the presence of binary catalytic system
HG2/PtO to form long-chain primary alcohols were reported as
an efficient catalytic protocol for the synthesis of fatty alcohols.
2
Hacettepe University, Faculty of Science, Chemistry Department, 06800,
Beytepe-Ankara, Turkey. E-mail: bengi04@hacettepe.edu.tr
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1nj00255d
2
2
6
5992
|
New J. Chem., 2021, 45, 5992–6000
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
Paper
NJC
Considering the importance of unsaturated alcohol deriva- and amines to form esters, imines and amides based on their
3
7,38
tives in various transformation reactions, the combination of donating groups.
The idea of using Grubbs type catalysts in
dehydrogenative coupling and cross-metathesis reactions in a dehydrogenative alcohol coupling reactions was evolved from
one-pot procedure will lead to the formation of various func- the study of Fogg et al. which describes the decomposition
tional materials. The proposed sequential reactions can be pathways of Grubbs type catalysts with primary alcohols, followed
39,40
possible by the in situ transformation of Grubbs catalysts to by subsequent formation of ruthenium hydride species.
Dehy-
ruthenium hydride species to catalyze the dehydrogenative drogenative alcohol coupling reactions can be catalyzed by in situ
coupling reactions after cross-metathesis reactions. In this generated ruthenium hydride species from Grubbs catalysts.
study, we have evaluated the performance of Grubbs catalysts Moreover, olefin metathesis reactions can be combined with
on dehydrogenative alcohol coupling reactions for the first time dehydrogenative coupling reactions in a one-pot procedure for
in literature. Dehydrogenative alcohol coupling and cross- the transformation of olefinic alcohols into complex structures.
metathesis reactions were combined in a one-pot procedure
1-Octanol was chosen as the model substrate for the optimi-
for the synthesis of functional ester molecules from unsaturated zation of dehydrogenative alcohol coupling reactions using a
alcohol derivatives using ruthenium based olefin metathesis variety of metathesis catalysts and bases. A toluene solution of
catalysts. Various saturated and unsaturated alcohol derivatives 1-octanol (1a, 0.244 M) in the presence of KOH (50% mol) and
2 3 2 3
and a set of different bases (NaOH, KOH, Cs CO , K CO , KOtBu, G1 (5% mol) was reacted at 110 1C under a nitrogen atmosphere.
NaOMe) were used for the optimization of the dehydrogenative After 6 h, 1-octanol was completely consumed and Guerbet alcohol;
alcohol coupling reactions. The mechanistic aspects of Grubbs 2-hexyl-1-decanol (2a) was formed in quantitative yield instead of
catalyzed dehydrogenative alcohol coupling reactions were inves- ester product. At the early stages of the reactions, 1-octanal was
tigated in detail. To the best of our knowledge, this study observed as an intermediate product but then rapidly consumed to
represents the first example of one-pot cross-metathesis/dehydro- form corresponding Guerbet alcohol (2a) in 95% yield.
genative alcohol coupling reactions using Grubbs type catalysts.
2 3 2 3
A variety of different bases (Cs CO , Na CO , KOtBu, NaOMe,
NaOH and KOH) were tested under identical reaction conditions
and results are given in Table 1. The reaction favored the
formation of the corresponding ester product; octyl octanoate
Results and discussion
(3a), through the dehydrogenative coupling of 1-octanol in the
Ruthenium based metathesis catalysts have emerged as efficient presence of weak bases (Na CO and Cs CO ). However, the
2
3
2
3
initiators for both olefin metathesis and non-metathetic trans- overall yield of the reaction was only 48% even after 48 h. In
2
7–29
formation reactions.
The potential of Grubbs catalysts in comparison to the weak base assisted G1 catalyzed dehydro-
non-metathetic reactions including hydrogenation, carboxylic genative coupling reactions, the formation of Guerbet alcohol
acid addition and cyclotrimerization reactions has been investi- was predominant when strong bases (KOH, NaOH, KOtBu and
3
0–34
gated in our research group.
Within this study, we have NaOMe) were employed under optimized reaction conditions.
To promote the ester formation in G1 catalyzed coupling
investigated the performance of Grubbs type ruthenium catalysts
on dehydrogenative alcohol coupling reactions. Furthermore, reactions, 10 mol% PCy was added to stabilize the catalytic
3
sequential cross-metathesis/dehydrogenative alcohol coupling intermediates and the reactions were repeated under identical
reactions were performed in a one-pot procedure for the synthesis reaction conditions. However, the addition of PCy3 didn’t
of functional ester derivatives for the first time in literature. improve the yield and the selectivity of the reaction.
The selectivity of dehydrogenative alcohol coupling reactions of
primary alcohols towards the formation of ester or b-alkylated
dimeric alcohol strictly depends on catalyst type and reaction Table 1 G1 catalyzed dehydrogenative alcohol coupling reactions of 1-
3
5
octanol
conditions. Our first attempts were focused on the optimization
of dehydrogenative alcohol coupling reactions of 1-octanol in the
presence of Grubbs first generation catalyst (G1) (Scheme 1).
As can be seen in literature examples, ruthenium hydride
species play a key role in dehydrogenative alcohol coupling
3
6
reactions. Ruthenium hydride complexes decorated with
Pincer ligands can selectively catalyze coupling of alcohols
a
b
Entry
Base
Time (h)
Conv. (%)
2a (%)
3a (%)
1
2
3
4
5
6
7
KOH
KOtBu
NaOMe
6
6
8
48
48
48
24
48
99
99
95
50
25
23
5
98
94
90
—
—
—
—
—
—
—
—
48
24
20
—
55
Cs
Na
CO
2
CO
3
2
CO
3
K
2
3
—
Cs
c
8
2
CO
3
/PCy
3
60
a
Conversion was determined by GC-MS using n-tetradecane as internal
b
c
3
standard. GC yield. 10% (mol%) PCy in 0.5 mL toluene was added
Scheme 1 Ruthenium based metathesis catalysts that are used in this study. to the reaction medium.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 5992–6000 | 5993

View Article Online
NJC
Paper
On the next trial, the performance of HG2 was tested on Table 3 Dehydrogenative alcohol coupling of 1-octanol in the presence
of various metathesis catalysts
coupling reactions of 1-octanol using identical reaction conditions
and results are given in Table 2. Unlike G1/KOH and G1/KOH/
PCy catalyzed dehydrogenative alcohol coupling reactions, the
3
addition of 10 mol% PCy in HG2 catalyzed coupling reactions
3
drastically increased the yield of the ester product (3a) up to 95%
(
Table 2, entry 8). When compared to the phosphine-free catalytic
process, the addition of 10 mol% PCy to the reaction media
improved the reaction yield and shortened the reaction time to
hours for the complete consumption of the starting materials. In
a
b
Catalyst
Base
KOH
Time (h)
Conv. (%)
2a
3a
3
G1
G1
M1
6
48
6
48
12
48
48
48
48
48
99
50
99
46
99
48
65
50
64
52
98
—
98
10
90
25
—
—
4
—
48
—
35
—
20
55
47
58
26
Cs
2
CO
3
8
KOH
some cases, potassium octanoate was formed as the side-product M1
and isolated as octanoic acid in 17% yield after acidification of the
reaction mixture with 3 N HCl. More detailed experimental results
were provided in Tables 3 and 4. The carboxylic acid formation HG2
mechanism was given in ESI,† section (Scheme S3, ESI†).
Alcohol coupling reactions can follow two different catalytic
pathways. The first pathway includes Tishchenko reactions
through the coupling of two aldehyde molecules to generate
ester derivatives in the presence of transition metals, alkali
alkoxides and lanthanide alkoxides.
utilizes hemiacetal intermediates through the reaction of alde-
hydes with alcohols, followed by dehydrogenation reaction to coupling of benzyl alcohol
Cs CO3
2
G2
G2
HG2
KOH
Cs
2
CO
3
KOH
Cs CO3
2
Aquamet
Aquamet
KOH
Cs
2
CO
3
3
a
Determined by GC-MS using n-tetradecane as the internal standard.
b
GC yield.
4
1–43
The second pathway
Table 4 The effect of different bases on the selectivity of dehydrogenative
1
6
form the final ester product. To determine the plausible
mechanism for the coupling reactions, control experiments
were carried out using 1-octanal and 1-octanal/1-octanol
2 3
mixture in the presence of Cs CO (Scheme 2).
The reaction of 1-octanal in the absence of G1 didn’t give
any ester product even after 48 h. The reaction was repeated Entry
using 5% mol G1 under identical reaction conditions and only
b
Base
KOH
3b %
4b %
Conversion (%)
a
1
82
29
93
94
81
8
90
36
96
94
100
a trace amount of ester product (3a) was observed after 48 h.
This result isn’t surprising since alcohol derivatives are needed
to generate ruthenium hydride species from Grubbs type
2
3
4
5
K2CO3
CS CO
KOtBu
NaOCH
—
—
—
2
3
c
3
19
3
9,40
catalysts.
These observations showed us that reaction
a
Benzoic acid (4b) was formed at the early stages of the reaction as
determined by GC-MS analysis. However, benzoic acid was consumed
after 12 h of reaction time. Determined by GC-MS. Methyl benzoate
doesn’t follow Tishchenko coupling mechanism. To prove that
the reaction mechanism involves the hemiacetal pathway,
b
c
1
-octanol and 1-octanal were reacted in the absence of G1. was formed in this reaction.
Ester product (3a) was obtained in 36% yield after 24 h. The
Table 2 HG2 catalyzed dehydrogenative alcohol coupling reactions of yield of 3a was increased up to 46% when the same reaction of
1
-octanol
equal amounts of 1-octanol/1-octanal was carried out in the
presence of 5% mol G1.
2 3
These results suggested that the G1/Cs CO catalyzed dehy-
drogenative coupling of alcohols proceeds through the reaction
of aldehyde with alcohol to form a hemiacetal derivative,
followed by catalytic dehydrogenation to give ester compound.
Similar mechanistic observations regarding the ruthenium
catalyzed dehydrogenative alcohol coupling reactions were also
b
Yield (%)
Additive Time (h) Conv. (%) 2a 3a 4a
a
Entry Base
1
6,44
1
2
3
4
5
6
7
8
9
KOH
KOH
KOtBu
KOtBu
NaOMe
—
PCy
—
PCy
—
24
8
65
99
50
63
40
94
47
95
0
—
—
—
—
—
—
—
—
—
55 10 reported in the literature.
It is important to note that the
3
3
3
82 17
addition of G1 in 1-octanol/1-octanal mixture didn’t signifi-
cantly increase the reaction yield. These results suggested that
the catalytic intermediate that was formed upon reaction of
alcohol/base with G1 doesn’t exhibit high activity. The tuning
of the ligand environment of the catalytic intermediate is
necessary to obtain reasonable reaction rates. The substitution
48
12
48
24
48
12
48
50
63
38
94
47
95
—
—
—
—
—
—
—
—
NaOMe PCy
Cs
Cs
—
2
CO
CO
3
—
PCy
PCy
2
3
3
3
a
3
of PCy ligand with better s-donor NHC ligands in the case of
HG2 improved the yield of the same reaction up to 90%
Conversion was determined by GC-MS using n-tetradecane as the
b
internal standard. GC yield.
5994
|
New J. Chem., 2021, 45, 5992–6000
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
Paper
NJC
Scheme 4 The proposed reaction mechanism for dehydrogenative cou-
pling of alcohols.
To gain more insight into the in situ formation of ruthenium
hydride species from Grubbs catalysts, a mechanistic study was
1
31
8
carried out using H and P NMR in toluene-d . Dehydrogena-
tive coupling of 1-octanol in the presence of G1/KOH in
Scheme 2 Mechanistic control experiments.
deuterated toluene (toluene-d ) was chosen as the representa-
8
tive reaction. Samples were withdrawn from the reaction
1
31
mixture at regular intervals and analyzed by H and P NMR.
After 10 minutes of reaction time, ruthenium alkylidene proton
signal appearing at 20.00 ppm disappeared and three different
ruthenium hydride signals were observed at À8.14 (t, 22.3 Hz,
major), À10.62 (d, 32.1 Hz, minor) and À15.82 (s, minor) ppm
(Scheme 5). Similar observations regarding the formation of
ruthenium hydride species from Grubbs catalysts were also
3
9,40
reported in the literature.
The mechanistic NMR studies of
G1/Cs CO mixture yielded the same ruthenium hydride inter-
2
3
mediate as confirmed by the proton signal appearing at À8.16
1
(
t, J = 22.5 Hz) ppm in H NMR. The minor hydride signals
Scheme 3 Reactions of 1-octanol and 1-octanal in the presence of G1
and HG2.
(Scheme 3) Similar results were also obtained with the mecha-
nistic studies regarding HG2 (Schemes S2 and S3, ESI†)
The proposed reaction mechanism for ester formation reac-
tion was given in Scheme 4. The ruthenium hydride species
were formed upon exchange of chloride ligands in Grubbs type
complexes with alkoxide ligands. The decomposition of G1 and
G2 to yield well-defined ruthenium monocarbonyl hydride
species in the presence of primary alcohols was first described
4
4,45
by Mol in 2003.
Similar ruthenium hydride generation
1
6
39,40
mechanisms were also proposed by Madsen and Fogg.
The alcohol was coordinated to the ruthenium center as the
alkoxide ligand. Aldehyde substituted complex was formed
through rearrangement of alkoxide ligand by b-hydride elimina-
tion. The nucleophilic attack of second alcohol to carbonyl
carbon yielded hemiacetal intermediate. The ester formation
proceeded simultaneously with b-hydride elimination.
1
Scheme 5 H NMR spectrums of in situ formed ruthenium hydride
8
species in toluene-d .
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 5992–6000 | 5995

View Article Online
NJC
Paper
(
À10.62 and À15.82 ppm) were not observed in the G1/Cs
2 3
CO
mixture even after 8 h. An alternative ruthenium hydride
formation mechanism from second generation Grubbs catalyst
analogs through dissociation of asymmetric NHC ligand was
reported by Maudit et al. However, no sign of NHC ligand
dissociation was observed in our mechanistic studies.
4
6
The reaction of G1/KOH with 1-octanol after 5 minutes
yielded four different phosphine species as confirmed by
3
1
in situ P NMR analysis. The major phosphine peak appearing
at 68.98 ppm can be related to the major ruthenium hydride
Scheme 7 Guerbet alcohol formation mechanism.
3
9,40
species decorated with tricyclohexylphosphine ligand.
The
other peaks appearing at 75.98 and 48.66 ppm indicated the
presence of possible phosphine decorated ruthenium hydride with this mechanism, ruthenium hydride formation in HG2/
species. The presence of free tricyclohexylphosphine was base system proceeds slower than G1/base systems as con-
1
observed at 9.83 ppm (Scheme 6). In the case of G1/Cs
2
CO
3
,
firmed by mechanistic H NMR studies. We believe that as a
two similar peaks were observed at 68.97 and 49.96 ppm result of this slow initiation step, no Guerbet alcohol was
and two additional peaks appeared at 64.25 and 42.39 ppm. observed during the reaction of 1-octanol and KOH in the
G1/Cs CO
2 3
and G1/KOH promoted dehydrogenation reactions presence HG2 bearing a chelating isopropoxyphenyl based
showed us that similar catalytic intermediates take role in ligand. In line with our observations, free 1-octanal was also
dehydrogenation reactions and the base strength has a sub- observed in G1/KOH catalyzed coupling reactions of 1-octanol.
stantial effect on product selectivity on dehydrogenative alcohol
The mechanism for Guerbet alcohol formation reactions is
coupling reactions. According to the mechanistic studies, the outlined in Scheme 7. Ruthenium catalyst involves in dehydro-
quantitative formation of ruthenium hydride species requires genation of alcohol to aldehydes. In the presence of strong
an excess of alcohol and base.
Guerbet alcohol formation is favored when KOH or other to yield an unsaturated aldehyde intermediate. This inter-
strong bases are used instead of Cs CO
in G1 catalyzed mediate then undergoes ruthenium catalyzed hydrogenation
-octanol coupling reactions. As previously reported by Fogg reaction to yield Guerbet alcohol product.
et al., the reaction of G1 with methanol/methoxide which
HG2/KOH/PCy (5/50/10%; mol/mol/mol%) system was cho-
involves the formation of ruthenium-aldehyde intermediate sen for the selective formation of ester derivatives through
bases, two molecules of aldehyde undergo Aldol condensation
4
7
2
3
1
3
4
0
proceeds faster than that of G2. The rapid formation of dehydrogenative alcohol coupling reactions of various alcohols.
aldehyde derivatives in G1 catalyzed dehydrogenation reactions A variety of alcohol derivatives; 1-hexanol (1c), isoamyl alcohol
using strong bases promote the aldol condensation reactions. (1d), 10-undecen-1-ol (1e), 1,4-butanediol (1f), cinnamyl alcohol
Therefore, aldol condensation reactions may proceed faster (1g) were used in further reactions and results are given in
than hemiacetal formation/dehydrogenation reactions in the Scheme 8. 1-Hexanol (1c) and isoamyl alcohol (1d) were rapidly
presence of strong bases (KOH, KOtBu and NaOMe). In line converted to the corresponding ester derivatives (2c and 2d) in
88% and 90% yields after 12 h of reaction time using 10% PCy
3
,
5
0% KOH and 5% HG2 in toluene. In the absence of PCy , the
3
reaction proceeded ineffectively, giving only 2c (55%) and 2d
55%) after 48 h of reaction time under identical reaction
conditions. The dehydrogenative coupling of olefinic alcohols;
-cinnamyl alcohol (1g) and 10-undecen-1-ol (1e) were
(
1
31
Scheme 6
toluene-d
2 3
P NMR spectrum of G1/KOH and G1/Cs CO mixture in
8
.
Scheme 8 HG2 catalyzed dehydrogenative coupling of various alcohols.
5996
|
New J. Chem., 2021, 45, 5992–6000
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
Paper
NJC
performed using HG2/KOH/PCy
3
under a constant flow of the constant nitrogen flow, at the early stages of the reaction,
nitrogen for the removal of evolved hydrogen gas to prevent nonalal and hydrogenation product; 1-nonanol were formed and
undesired hydrogenation of double bonds. The reaction was then rapidly consumed to form nonyl nonanoate.
completed within 12 h yielding corresponding unsaturated
After 24 h, the conversion of nonalal and 1-nonanol was
ester derivatives 2e and 2g in 92% and 95% yield. Corres- reached a plateau and corresponding saturated ester product;
ponding carboxylic acids were formed in 8% and 5% yield in nonyl nonanoate was obtained in 85% yield. Although the
2
e and 2g. It is important to note that no metathesis side reaction reactions were carried out under static nitrogen flow, all double
was observed during dehydrogenative coupling of unsaturated bonds were hydrogenated very rapidly after the metathesis
alcohol derivatives. reaction. Despite our countless efforts, the isomerization reac-
,4-Butanediol yielded g-butyrolactone in higher yields in tions of double bonds couldn’t be suppressed.
1
the both presence and absence of PCy (yields: 98% and 95%)
As it can be seen in Scheme 8, dehydrogenative coupling of
3
through the coupling of alcohol groups in an intramolecular 1,4-butanediol yields g-butyrolactone. We have foreseen that
fashion. It is interesting to note that 1,6-hexanediol yielded sequential self-metathesis of allyl alcohol followed by subse-
oligomeric unidentified product mixture instead of caprolac- quent dehydrogenative coupling reactions can be a model
tone under both reaction conditions (HG2/KOH/PCy
mol%, 5/50/10 and 5/50/–).
3
; mol/mol/ reaction to build lactone derivatives efficiently (Scheme 10).
For this purpose, the self-metathesis of allyl alcohol was
Cross-metathesis of olefinic alcohol derivatives were inten- studied under ambient reaction conditions. A Schlenk reactor
2
4–26
sively studied by several research groups.
G1 was reported as was charged with allyl alcohol (0.25 M) in toluene and HG2
an inefficient initiator for cross-metathesis of olefinic alcohols in (5%) and reacted at 30 1C. After one hour, allyl alcohol was
terms of reaction yield and selectivity. In most cases, aldehydes completely consumed and self-metathesis product; 2-butene-
and undefined side-products were obtained in G1 catalyzed 1,4-diol was obtained as the major product and a trace amount
metathesis reactions. On the other hand, HG2 performed of 1,4-butanediol was observed. A suspension of KOH (50%) in
cross-metathesis and self-metathesis of olefinic alcohols in toluene was added to the reactor and the reaction temperature
quantitative yields in a short amount of time without any side was increased to 110 1C. At the early stages of the reaction,
products. Considering the above-mentioned facts, HG2 was 2-butene-1,4-diol was hydrogenated to 1,4-butanediol. After
chosen as the initiator for sequential cross-metathesis/dehydro- 24 h, g-butyrolactone was obtained with an overall yield of 88%.
genative coupling reactions. Cross-metathesis of various olefinic
The compatibility of dehydrogenative coupling reactions
alcohol derivatives such as oleyl alcohol, cinnamyl alcohol, allyl with ethenolysis reactions was investigated using cinnamyl
alcohol were studied intensively using HG2 as the metathesis alcohol and oleyl alcohol as the model substrates under an
initiators. HG2 (5%) catalyzed cross-metathesis of allyl alcohol ethylene atmosphere. Ethenolysis of cinnamyl alcohol was
and 1-octene (10 fold excess) at 30 1C yielded 2-nonen-1-ol as the performed in toluene under ethylene atmosphere (1 atm) at
major product along with self-metathesis product of 1-octene; 80 1C (Scheme 11). Cinnamyl alcohol was completely converted
7-tetradecene after 2 h. (Scheme 9). An excess of 1-octene was to ethenolysis products; styrene and allyl alcohol within
used to suppress the self-metathesis of allyl alcohol. Following 30 minutes of reaction time. The reactor was charged with
the complete consumption of allyl alcohol and subsequent 50% KOH and 10% PCy3 and the reaction temperature was
formation of 2-nonel-1-ol, KOH (50%) and PCy (10%) in toluene increased to 110 1C under a nitrogen atmosphere to initiate the
3
were added to the reactor and the temperature of the reaction dehydrogenative coupling reactions. Although hydrogenation
mixture was increased to 110 1C to initiate the dehydrogenative
alcohol coupling reactions under constant nitrogen flow. Despite
Scheme 10 One-pot self-metathesis/dehydrogenative coupling of allyl
alcohol.
Scheme 9 One-pot cross-metathesis/dehydrogenative alcohol coupling
Scheme 11 One-pot ethenolysis/dehydrogenative coupling of cinnamyl
of allyl alcohol/1-octene.
alcohol and oleyl alcohol.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 5992–6000 | 5997

View Article Online
NJC
Paper
products; ethylbenzene and n-propanol were observed in GC over CaH
2
and distilled under nitrogen atmosphere. Gas
analysis, no dehydrogenative coupling products were formed chromatography-mass spectrometry (GC-MS) analyses were
even after 48 h of reaction time. performed with a Shimadzu GC-MS 2010Plus using a Restek
Oleyl alcohol is a more challenging substrate than cinnamyl Rxi-5Sil column (30 m  0.25 mm  0.25 mm) and temperature
alcohol in ethenolysis reactions due to its isomerization ten- range of 50–320 1C with a constant helium flow rate of
À1
1
13
31
dency (Scheme 11). Ethenolysis of oleyl alcohol under ethylene 1 mL min . H, C and P NMR spectra were recorded at
atmosphere (1 atm) yielded an isomeric mixture of both starting 25 1C with a Bruker GmbH 400 MHz high performance digital
material and ethenolysis products (50% conversion, 80% iso- FT-NMR spectrometer using CDCl
merization). On the next trial, ethylene gas was continuously solvents.
bubbled throughout the reaction to suppress isomerization
3 8
and toluene-d as NMR
reactions, however, a significant amount of isomerization
product was obtained again (65% isomerization). The pressure
of ethylene gas was increased to 4 atm to increase the reaction
Representative procedure for Ru-catalyzed dehydrogenative
alcohol coupling reactions
yield and suppress isomerization. However, all our efforts to Ruthenium catalyst (0.0122 mmol), KOH (0.122 mmol, 0.0068 g)
suppress undesired olefin isomerization have failed. One of the and 1-octanol (0.244 mmol, 38 mL) in dry toluene (1 mL) were
known methods for suppressing olefin isomerization during the added to a glass Schlenk reactor under nitrogen atmosphere.
metathesis reaction is to use 1,4-benzoquinone as the hydride The reactor was heated to 110 1C in a preheated oil bath and
4
8,49
scavenger.
However, ruthenium hydride is the key species in magnetically stirred. Samples regularly were withdrawn from the
our sequential cross-metathesis/dehydrogenative coupling reac- reaction mixture, diluted with methanol and analyzed by GC/MS.
tions, therefore we didn’t employ benzoquinone as the isomeriza- Once the conversion of 1-octanol has reached a plateau, toluene
tion suppressor. The addition of solely 50% KOH or KOH/PCy3 was removed by a high vacuum and the residual content was
(
50/10; mol/mol) to the above-mentioned reaction mediums dissolved in CH
Cl and acidified with 3 N HCl to pH 2–3 for the
2 2
triggered the formation of isomerization reactions however no isolation of carboxylic acid side products. The organic phase was
dehydrogenative coupling product was formed.
extracted with water (5 mL Â 3) to remove the excess KOH. The
organic phase of the solution was passed through a plug of silica
gel to remove any catalytic impurities and then the organic phase
Conclusion
4 2 2
was dried by the addition of MgSO . CH Cl was removed under
high vacuum and reaction product was analyzed by GC-MS
In summary, Grubbs catalysts performed the dehydrogenative
alcohol coupling and one-pot cross-metathesis/dehydrogena-
tive coupling reactions of various alcohol derivatives selectively
for the first time in literature. The selectivity of G1 was tuned by
varying base in the dehydrogenative coupling of 1-octanol to
produce b-alkylated alcohols (Guerbet) with strong bases (up to
1
and H NMR in CDCl . Products were isolated using dry
3
column vacuum chromatography (DCVC) starting from 100%
n-hexane as the non-polar phase, followed by increasing the
polarity of the mobile phase (5% for each addition) with ethyl
acetate.
95% yield) and ester derivatives with weak bases (up to 95%
yield). The in situ formation of ruthenium hydride species
Representative procedure for HG2/PCy -catalyzed
3
during G1 and HG2 catalyzed coupling reaction was confirmed
by H NMR mechanistic studies. Following the optimization of
dehydrogenative alcohol coupling reactions
1
HG2 (0.01 g, 0.0122 mmol), KOH (0.122 mmol, 0.0068 g), PCy
0.068 g, 0.0244 mmol) and 1-octanol (0.244 mmol, 38 mL) in dry
3
reaction conditions, one-pot cross-metathesis/dehydrogenative
alcohol coupling reaction were investigated using allyl alcohol,-
cinnamyl alcohol and oleyl alcohol as the olefinic substrates.
The one-pot dehydrogenative coupling/self-metathesis of allyl
alcohol gave g-butyrolactone in excellent yield using 5% HG2,
(
toluene (1 mL) were added to a glass Schlenk reactor under
nitrogen atmosphere. The reactor was heated to 110 1C in a
preheated oil bath and magnetically stirred. Samples regularly
were withdrawn from the reaction mixture, diluted with methanol
and analyzed by GC/MS. Once the conversion of 1-octanol
has reached a plateau, toluene was removed by a high vacuum
50% KOH and 10% PCy
3
. The sequential cross-metathesis of
1-octene with allyl alcohol and dehydrogenative coupling reac-
tions gave nonyl nonanoate in 85% yield. It is noteworthy that
all double bonds of olefinic alcohols were saturated during
dehydrogenative coupling reactions. Although ethenolysis of
cinnamyl alcohol and oleyl alcohol proceeded rapidly with HG2
under ethylene atmosphere, in situ formed allyl alcohol and
2 2
and the residual content was dissolved in CH Cl and the organic
phase was extracted with water (5 mL Â 3) to remove the excess
KOH. The organic phase of the solution was passed through a
plug of silica gel to remove any catalytic impurities and then the
organic phase was dried by the addition of MgSO
4 2 2
. CH Cl was
9-decen-1-ol didn’t undergo dehydrogenative coupling reactions.
removed under high vacuum and reaction product was analyzed
1
3
by GC-MS and H NMR in CDCl . Products were isolated using
dry column vacuum chromatography (DCVC) starting from
n-hexane as the non-polar phase, followed by increasing the
Experimental section
Otherwise noted all chemicals were purchased from Sigma- polarity of the mobile phase gradually (5% for each addition)
Aldrich and used as received. Toluene and p-xylene were dried with ethyl acetate.
5998
|
New J. Chem., 2021, 45, 5992–6000
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
Paper
NJC
Representative procedure for the ruthenium-catalyzed
dehydrogenative alcohol coupling reactions
Representative procedure for ethenolysis and one-pot ethenolysis/
dehydrogenative coupling of cinnamyl alcohol and oleyl alcohol
1
5
-Octanol (0.244 mmol, 38 mL) and benzyl alcohol (0.488 mmol, A Schlenk reactor was charged with cinnamyl alcohol (0.320 mmol,
1 mL) were added to a glass Schlenk reactor under a nitrogen 0.043 g) in dry toluene (2.0 mL). Ethylene gas (1 atm) was bubbled
atmosphere and magnetically stirred for five minutes at room through the reaction mixture for 5 minutes before the introduc-
temperature. KOH (0.122 mmol, 0.0068 g), PCy (0.068 g, tion of HG2 (0.0160 mmol, 0.010 g) in toluene (0.5 mL). The
.0244 mmol) and G1 (0.01 g, 0.0122 mmol) were added in reaction mixture was then taken to a pre-heated oil bath at 80 1C
3
0
one portion to the reactor and the reaction mixture was stirred to initiate the ethenolysis reactions. After 2 h, cinnamyl alcohol
at 110 1C under nitrogen atmosphere. Samples were regularly was completely converted to the desired ethenolysis products;
withdrawn from the reaction mixture, diluted with methanol styrene and allyl alcohol as confirmed by GC-MS analysis. After
and analyzed by GC-MS. Products were isolated using dry column that, the reaction of the temperature was increased to 110 1C and
vacuum chromatography (DCVC) starting from n-hexane as the KOH (0.160 mmol, 0.0090 g) and PCy
3
(0.0320 mmol, 0.0090 g)
non-polar phase, followed by increasing the polarity of the mobile was added to the reactor. Samples were regularly withdrawn from
phase (5% for each addition) with ethyl acetate.
the reaction mixture and analyzed by GC-MS.
Representative procedure for NMR mechanistic studies
Representative procedure for the metathesis and cross-metathesis/
dehydrogenative alcohol coupling reactions
G1 (0.01 g, 0.0122 mmol), KOH (0.122 mmol, 0.0068 g) and
1
-octanol (0.244 mmol, 38 mL) in toluene-d (1 mL) were added to
8
Cross-metathesis of 1-octene and allyl alcohol. Allyl alcohol
0.500 mmol, 34 mL), 1-octene (0.955 mmol, 150 mL) and dry
a glass Schlenk reactor under nitrogen atmosphere. The reactor
was heated to 110 1C in a preheated oil bath and magnetically
stirred. Samples regularly were withdrawn from the reaction
mixture and the samples were diluted with toluene-d and
8
analyzed by H and P NMR.
(
toluene (1.5 mL) were mixed in a glass Schlenk reactor and
stirred for five minutes at 30 1C. HG2 (0.0160 mmol, 0.010 g) in
toluene (0.5 mL) was added to the reactor in one portion and
the reaction mixture was magnetically stirred for 1 h at 30 1C.
Samples were regularly withdrawn from the reaction mixture
and analyzed by GC-MS.
1
31
Conflicts of interest
One-pot cross-metathesis/dehydrogenative alcohol coupling
reactions of allyl alcohol and 1-octene. Allyl alcohol There are no conflicts to declare.
0.500 mmol, 34 mL), 1-octene (0.955 mmol, 150 mL) and dry
(
toluene (1.5 mL) were mixed in a glass Schlenk reactor and
stirred for five minutes at 30 1C. HG2 (0.0160 mmol, 0.010 g) in
toluene (0.5 mL) was added to the reactor in one portion and
the reaction mixture was magnetically stirred. Following the
complete consumption of allyl alcohol after 1 h, a suspension
Acknowledgements
We would like to thank The Scientific and Technological
Research Council of TURKEY (TUBITAK) for the financial
support of this work (TUBITAK 1002 program, Project No:
of KOH (0.250 mmol, 0.014 g) and PCy (0.050 mmol) in 0.5 mL
3
119Z655).
toluene was added to the reactor and the temperature was
increased to 110 1C. Samples were regularly withdrawn from
the reaction mixture and analyzed by GC-MS.
Notes and references
Self-metathesis of allyl alcohol. Allyl alcohol (0.320 mmol,
2
2 mL) and dry toluene (2.0 mL) were mixed in a glass Schlenk
reactor and stirred for five minutes at 30 1C. HG2 (0.0160 mmol,
.010 g) in toluene (0.5 mL) was added to the reactor in one
portion and the reaction mixture was magnetically stirred for
h at 30 1C. Samples were regularly withdrawn from the
1 S. M. A. H. Siddiki, T. Toyao and K.-I. Shimizu, Green Chem.,
2018, 20, 2933–2952.
2 M. K. Lakshman and P. K. Vuram, Chem. Sci., 2017, 8,
5845–5888.
3 S. Shu, M. Huang, J. Jiang, L.-B. Qu, Y. Liu and Z. Ke,
Catal. Sci. Technol., 2019, 9, 2305–2314.
0
1
reaction mixture and analyzed by GC-MS.
One-pot self-metathesis/dehydrogenative alcohol coupling
reactions of allyl alcohol. Allyl alcohol (0.32 mmol, 22 mL) and
dry toluene (2.0 mL) were mixed in a glass Schlenk reactor and
stirred for five minutes at 30 1C. HG2 (0.0160 mmol, 0.010 g) in
toluene (0.5 mL) was added to the reactor in one portion and
reaction mixture was magnetically stirred for 1 h at 30 1C. Following
the complete consumption of allyl alcohol after 1 h, a suspension of
4 S. K. Moromi, S. M. A. H. Siddiki, A. Ali, K. Kon and
K.-I. Shimizu, Catal. Sci. Technol., 2014, 4, 3631–3635.
5 T. Matsu-ura, S. Sakaguchi, Y. Obora and Y. Ishii, J. Org.
Chem., 2006, 71, 8306–8308.
6 U. K. Das, Y. Ben-David, G. Leitus, Y. Diskin- Posner and
D. Milstein, ACS Catal., 2019, 9, 479–484.
7 K. Paudel, B. Pandey, S. Xu, D. K. Taylor, D. L. Tyer,
C. L. Torres, S. Gallagher, L. Kong and K. Ding, Org. Lett.,
2018, 20, 4478–4481.
KOH (0.160 mmol, 0.0090 g) and PCy (0.0320 mmol, 0.0090 g) in
3
0.5 mL toluene was added to the reactor and the temperature was
increased to 110 1C. Samples were regularly withdrawn from the
reaction mixture and analyzed by GC-MS.
8 S. Musa, L. Ackermann and D. Gelman, Adv. Synth. Catal.,
2013, 355, 3077–3080.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 5992–6000 | 5999

View Article Online
NJC
R. G. Alabau, M. A. Esteruelas, A. Mart ´ı nez, M. Oliv ´a n and 29 A. Mukherjee, Synlett, 2006, 1128–1129.
Paper
9
E. O n˜ ate, Organometallics, 2018, 37, 2732–2740.
0 D. Srimani, E. Balaraman, B. Gnanaprakasam, Y. Ben-David 31 B. O. Ozt u¨ rk, D. G u¨ rc u¨ and S. K. -Sehitoglu, J. Organomet.
and D. Milstein, Adv. Synth. Catal., 2012, 354, 2403–2406. Chem., 2019, 883, 11–16.
1 X. He, Y. Li, H. Fu, X. Zheng, H. Chen, R. Li and X. Yu, 32 S. Karabulut, B. O. Ozt u¨ rk and Y. Imamoglu, J. Organomet.
Organometallics, 2019, 38, 1750–1760. Chem., 2010, 695, 2161–2166.
2 X. Jiang, J. Zhang, D. Zhao and Y. Li, Chem. Commun., 2019, 33 B. O. Ozt u¨ rk, S. Karabulut and Y. Imamoglu, Appl. Catal., A,
5, 2797–2800. 2012, 433–434, 214–222.
3 Z. Q. Wang, X. S. Tang, Z. Q. Yang, B. Y. Yu, H. J. Wang, 34 B. O. Ozt u¨ rk, S. Karabulut and Y. Imamoglu, Inorg. Chim.
30 B. O. Ozt u¨ rk and S. Ozt u¨ rk, Mol. Catal., 2020, 480, 110640.
¨
¨
¨
¨
¨
1
1
1
1
˘
¨
¨
˙
˘
¨
¨
˙
˘
5
¨
¨
˙
˘
W. Sang, Y. Yuan, C. Chen and F. Verpoort, Chem. Commun.,
019, 55, 8591–8594.
4 C. Santilli, I. S. Makarov, P. Fristrup and R. Madsen, J. Org.
Chem., 2016, 81, 9931–9938.
5 J. Malineni, H. Keul and M. M ¨o ller, Dalton Trans., 2015, 44,
Acta, 2011, 378, 257–263.
2
35 K. R. Rohit, S. Radhika, S. Saranya and G. Anilkumar,
An Overview, Adv. Synth. Catal., 2020, 362, 1602–1650.
36 V. Arora, M. Dutta, K. Das, B. Das, H. K. Srivastava and
A. Kumar, Organometallics, 2020, 39, 2162–2176.
37 T. Higuichi, R. Tagawa, A. Limuro, S. Akiyama, H. Nagae
and K. Mashima, Chem. – Eur. J., 2017, 23, 12795–12804.
38 D. Spasyuk and D. G. Gusev, Organometallics, 2012, 31,
5239–5242.
1
1
1
1
7409–17414.
6 A. Sølvhøj and R. Madsen, Organometallics, 2011, 30,
044–6048.
7 S. Makarov and R. Madsen, J. Org. Chem., 2013, 78, 6593–6598.
6
1
1
8 W. Chang, X. Gong, S. Wang, L.-P. Xiao and G. Song, 39 N. J. Beach, J. A. M. Lummiss, J. M. Bates and D. E. Fogg,
Org. Biomol. Chem., 2017, 15, 3466–3471. Organometallics, 2012, 31, 2349–2356.
9 J. Shi, B. Hu, P. Ren, S. Shang, X. Yang and D. Chen, 40 N. J. Beach, K. D. Camm and D. E. Fogg, Organometallics,
Organometallics, 2018, 37, 2795–2806. 2010, 29, 5450–5455.
0 S. Manojveer, S. Salahi, O. F. Wendt and M. T. Johnson, 41 D. H. Nguyen, X. Trivelli, F. Capet, Y. Swesi, A. Favre-
1
2
2
2
2
2
2
2
2
2
J. Org. Chem., 2018, 83, 10864–10870.
R ´e guillon, L. Vanoye, F. Dumeignil and R. M. Gauvin,
ACS Catal., 2018, 8, 4719–4734.
1 O. M. Ogba, N. C. Warner, D. J. O’Leary and R. H. Grubbs,
Chem. Soc. Rev., 2018, 47, 4510–4544.
42 D. G. Gusev, ACS Catal., 2016, 6, 6967–6981.
2 Y. A. Lin and B. G. Davis, Beilstein J. Org. Chem., 2010, 6, 43 M.-O. Simon and S. Darses, Adv. Synth. Catal., 2010, 352,
219–1228. 305–308.
3 C. Xu, Z. Liu, S. Torker, X. Shen, D. Xu and A. H. Hoveyda, 44 M. B. Dinger and J. C. Mol, Organometallics, 2003, 22,
J. Am. Chem. Soc., 2017, 139, 15640–15643. 1089–1095.
4 A. Rybak and M. A. R. Meier, Green Chem., 2008, 10, 45 M. B. Dinger and J. C. Mol, Eur. J. Inorg. Chem., 2003,
099–1104. 2827–2833.
5 B. Schmidt and S. Hauke, Org. Biomol. Chem., 2013, 11, 46 M. Rouen, P. Queval, E. Borr ´e , L. Falivene, A. Poater,
194–4206.
6 R. Jia, Z. Zuo, X. Li, L. Liu and J. Dong, Chin. Chem. Lett.,
020, 31, 1525–1529.
1
1
4
M. Berthod, F. Hugues, L. Cavallo, O. Basl ´e , H. Olivier-
Bourbigo and M. Maudit, ACS Catal., 2016, 6, 7970–7976.
47 G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010, 110,
681–703.
2
7 A. A. Poeylaut-Palena, S. A. Testero and E. G. Mata,
Chem. Commun., 2011, 47, 1565–1567.
48 B. Schmidt, J. Mol. Catal. A, 2006, 254, 53–57.
8 B. Alcaide, P. Almendros and A. Luna, Chem. Rev., 2009, 109, 49 S. H. Hong, D. P. Sanders, C. W. Lee and R. H. Grubbs, J. Am.
3817–3858.
Chem. Soc., 2005, 127, 17160–17161.
6
000
|
New J. Chem., 2021, 45, 5992–6000
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021