Etherification reactions of propargylic alcohols catalyzed by a cationic ruthenium allenylidene complex

Article abstract of DOI:10.1016/j.catcom.2014.01.002

The cationic ruthenium allenylidene complex R_RuR _ax-[Ru(indenyl)L(PPh₃)CCCPh₂] ⁺PF₆ catalyzes the etherification of secondary and tertiary propargylic alcohols in a formal nucleophilic substitution reaction utilizing primary and secondary alcohols as the nucleophiles. At a catalyst loading of only 1.1 mol%, the corresponding propargylic ether products were obtained in 9 to 73% isolated yields (18 h reaction time at 100 C); no further additives are required. The reaction exhibits an induction period; as shown by a control reaction, the high reaction temperature may chemically change the allenylidene complex to be employed as the catalyst but does not lead to catalyst deactivation.

Full text of DOI:10.1016/j.catcom.2014.01.002

Catalysis Communications 47 (2014) 45–48
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Catalysis Communications
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Short Communication
Etherification reactions of propargylic alcohols catalyzed by a cationic
ruthenium allenylidene complex
⁎
Doaa F. Alkhaleeli, Kevin J. Baum, Jordan M. Rabus, Eike B. Bauer
University of Missouri — St. Louis, Department of Chemistry and Biochemistry, One University Boulevard, St. Louis, MO 63121, USA
a r t i c l e i n f o
a b s t r a c t
The cationic ruthenium allenylidene complex RRuRax−[Ru(indenyl)L(PPh3)_C_C_CPh2]+PF6 catalyzes
the etherification of secondary and tertiary propargylic alcohols in a formal nucleophilic substitution reaction
utilizing primary and secondary alcohols as the nucleophiles. At a catalyst loading of only 1.1 mol%, the
corresponding propargylic ether products were obtained in 9 to 73% isolated yields (18 h reaction time at
100 °C); no further additives are required. The reaction exhibits an induction period; as shown by a control
reaction, the high reaction temperature may chemically change the allenylidene complex to be employed as
the catalyst but does not lead to catalyst deactivation.
Article history:
Received 10 November 2013
Received in revised form 2 January 2014
Accepted 4 January 2014
Available online 11 January 2014
Keywords:
Propargylic substitution
Homogeneous catalysis
Ruthenium allenylidene complexes
Propargylic ethers
© 2014 Elsevier B.V. All rights reserved.
Propargylic alcohols (1 in Scheme 1) are valuable starting materials
in organic synthesis [1–4]. They are easily accessible, e.g. through addi-
tion of acetylides to ketones [5–7]. The functionalization and derivatiza-
tion of propargylic alcohols can quickly increase structural complexity
[8,9]; consequently, propargylic alcohols are often starting materials
for the synthesis of natural products or other complex organic molecules
[10]. The nucleophilic substitution of the \OH group in propargylic
alcohols is one way to modify the propargylic scaffold, as exemplified
by the etherification reaction shown in Scheme 1, where an alcohol is
the nucleophile and a propargylic ether 2 the product. Different mecha-
nisms for the reaction are discussed in the literature, and one suggested
mechanistic pathway proceeds through an allenylidene intermediate 3
(Scheme 1) [1,2]. However, the direct replacement of an \OH group in
propargylic alcohols can be challenging. Rearrangement reactions of
propargylic alcohols to aldehydes or ketones are often observed as
byproducts [1]. These rearrangement reactions to aldehyde and ketones
(referred to as Meyer–Schuster [11–13] and Rupe [14,15] rearrange-
ments) can be synthetically useful in their own right, but in the context
of propargylic substitution reactions they are yield-diminishing side
reactions.
propargylic alcohols by carbon- [16,17] oxygen- [18–20], phosphorus-
[21] or nitrogen-based nucleophiles [22], and a few enantioselective
catalyst systems have been reported as well [23,24]. Ruthenium, iron,
gold, copper and rhenium based complexes are the most widely used
catalyst systems [1,2].
Still, the number of catalyst systems for substitution reactions is
scarce, when compared to its sister reaction, i.e. allylic substitution reac-
tions [25]. Often high temperatures are required for catalytic activity [1],
and as a consequence, there is a need for reactive, tunable catalysts,
which eventually can be employed in enantioselective versions of the
title reaction.
As part of our longstanding research program, we are interested
in the catalytic and stoichiometric activation of propargylic alcohols by
ruthenium complexes [26–29]. Ruthenium complexes can form
allenylidene complexes [Ru_C_C_CR2] from propargylic alcohols
[30,31]. They can be attacked by nucleophiles and, thus, potentially
serve as intermediates in catalytic propargylic substitution reaction
cycles [1,4,30]. We have recently synthesized the cationic ruthenium
allenylidene complex RRuRax−[Ru(indenyl)L(PPh3)_C_C_CPh2]+PF6
(4, Fig. 1), where L is a phosphoramidite ligand [27,28].
Consequently, catalyst systems for propargylic substitution
reactions need to specifically catalyze the substitution while being
inefficient for the corresponding rearrangement reactions. Furthermore,
\OH groups are poor leaving groups, making their substitution more
difficult. As a consequence, the \OH group in propargylic alcohols is
often in a first step converted to a better leaving group prior to further
functionalization. Nevertheless, substantial progress has been made in
recent years towards the direct [1,3,4] replacement of \OH groups in
The complex is chiral at the metal and at the phosphoramidite ligand
and was obtained as a single diastereomer. Allenylidene complexes can
serve as catalysts for organic transformations, and we speculated as to
whether the cationic complex 4 could be catalytically active in the
etherification of propargylic alcohols through a propargylic substitution
reaction, using alcohols as nucleophiles. The complex is chiral and
tunable through the coordinated ligands, and we identified 4 as a
good candidate for investigations and for tuning efforts to be performed
in future research. Related cationic complexes have previously been
employed in propargylic substitution reactions [32,33]. We describe
herein the catalytic activity of the complex in the title reaction.
⁎
Corresponding author. Tel.: +1 314 516 5311; fax: +1 314 516 5342.
E-mail address: bauere@umsl.edu (E.B. Bauer).
1566-7367/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2014.01.002

46
D.F. Alkhaleeli et al. / Catalysis Communications 47 (2014) 45–48
Table 1
Isolated yields.
Entry a Substrate
1
R3\OH
Product
Isolated
yield
29%
41%
72%
Scheme 1. Propargylic etherification reaction and potential mechanism through an
allenlidene intermediate.
2
3
Screening efforts (which are not detailed here) were undertaken to
identify an appropriate solvent and a temperature for the etherification
reaction to be catalyzed by complex 4. We found that with toluene as a
solvent at a temperature of 100 °C complex 4 efficiently catalyzed the
reaction of a variety of propargylic alcohol 5 and alcohol 6 to give
the corresponding propargylic ethers 7 within 18 hour reaction time
(Table 1). At a catalyst loading of only 1.1 mol%, the reacting alcohols
were employed in a three to five-fold excess over the propargylic
alcohols, and the propargylic ether substitution products were isolated
by column chromatography. As assessed by GC, after 18 h at 100 °C,
the propargylic starting material had been completely consumed, and
a new peak for the product was detected. No side products were ob-
served except for some dehydration products for the cyclic propargylic
alcohols in entries 7 to 10 [14]. The isolated yields are lower than
the complete conversion observed by GC would suggest, and it might
be that some product decomposition occurs during purification by
column chromatography.
4
5
73%
21%
6
7
70%
65%
The identity of the propargylic ether products was readily
established by 1H and 13C{1H} NMR and by IR. The terminal alkyne
units gave characteristic chemical shifts, around 2.5 ppm for the termi-
nal proton and around 75 and 85 ppm for the two alkyne carbon atoms.
Furthermore, a characteristic υCH stretch in the IR spectra around
3300 cm−1 for the terminal `C\H unit was observed. No strong,
broad IR stretch around 3300 cm−1 originating from alcohols was
detected, indicating the absence of starting materials in the isolated
products.
Primary alcohols (ethanol, n-butanol and benzyl alcohol) and
secondary and tertiary propargylic alcohols gave the corresponding
propargylic ethers in 28 to 73% isolated yields (Table 1). The secondary
alcohol isopropanol gave lower isolated yields (9 to 21%) when reacted
with secondary or tertiary propargylic alcohols (entries 5 and 8). We
ascribe these lowered isolated yields to the decreased nucleophilicity
of the secondary alcohol isopropanol compared to the primary alcohols
employed in the study. Control experiments showed that the 18 hour
8
9%
9
56%
28%
10
a
Typical conditions: alkynol (0.7 mmol) and alcohol (3.3 mmol) in toluene (1 mL)
catalyzed by 4 (0.008 mmol), at 100 °C for 18 h. The products were isolated by column
chromatography.
reaction time reported in Table 1 is a requirement for efficient product
formation. Lower reaction times or lower temperatures resulted in an
incomplete reaction with propargylic starting material still remaining
in the reaction mixture, as assessed by GC measurements. The internal
propargylic alcohol 2-methylhex-3-yn-2-ol could not be converted
to ether products under the conditions in Table 1. An increase of the
catalyst load to 2 mol% did not result in a higher isolated yield, as
established for the reaction in entry 2 of Table 1. The catalyst system
described herein compares (with respect to reaction conditions and
yields) well with other catalysts reported in the literature [1,2,18–20].
However, the catalyst loading for 4 was only 1%, and with one exception
Fig. 1. Cationic ruthenium allenylidene complex RRu
current study.
Rax−4 investigated as a catalyst in the

D.F. Alkhaleeli et al. / Catalysis Communications 47 (2014) 45–48
47
To further explore the scope of the reaction and to gain some hints
about the catalytically active species and the mechanism, additional ex-
periments were performed. First, the reaction between the propargylic
alcohol 12 and the n-butanol was followed by 1H NMR measurements
in toluene-d8 over time under the same reaction conditions reported
in Table 1. Some conversion rates over time are reported in Table 2 (as
determined by integration of the `C\H signals of the starting material
12 and the product 13). The reaction seemed to exhibit an induction
period, as can be seen from the low conversions in the first 3 h of the
reaction. Further research is necessary to investigate the cause for the
induction period. It appears reasonable to assume that the catalytically
active species forms in the early stage of the reaction, causing a delay
in product formation. This assumption is corroborated by the fact, that
the 31P{1H} NMR signals of the catalyst 4 disappeared over time in the
experiment in Table 2. The catalyst 4 exhibits two doublets for the
two coordinated phosphorus atoms in the 31P{1H} NMR spectrum,
which completely disappeared by the end of the 18 hour reaction
time. The 31P{1H} NMR spectrum of the sample after heating at 100 °C
for 18 h exhibited signals for free PPh3 and oxidized PPh3 as well as
a peak resulting from the oxidation of the phosphoramidite ligand
(spectrum see supporting information). The spectrum, however,
does not establish a catalytically active ruthenium species nor allows
for the conclusion that the catalytically active species is ligand-free.
The 31P{1H} NMR signals for the active species could (due to the low
concentration of the catalyst in solution) also be hidden in the baseline.
We investigated further whether a chemical transformation of com-
plex 4 generates the catalytically active species for the reactions in
Table 1. We first heated the catalyst in toluene-d8 to 100 °C in the
absence of any substrates for 18 h (Scheme 3), after which the charac-
teristic doublets in the 31P{1H} NMR spectrum for complex 4 had disap-
peared. Then, the propargylic alcohol 12 and n-butanol were added to
the solution, and the mixture was heated for another 18 h. It was ob-
served that the complex 4, when first heated for 18 h, also completely
converted the propargylic alcohol 12 to the corresponding propargylic
ether. Besides the product, no propargylic alcohol starting material 12
was detected by GC and NMR. Thus, it appears that complex 4 might
decompose during heating over time, but the decomposition product
is still catalytically active. The decomposition product might even be
the only catalytically active species in solution, as judged from the
induction period established in Table 2.
Scheme 2. Reactivity of 1,1-diphenylprop-2-yn-1-ol (8).
Table 2
Product formation over time.
Time
Conversion to 13 (NMR)
90 min
0%
11%
46%
66%
100%
200 min
360 min
480 min
1300 min
[18], the other catalyst systems require catalyst loadings of 5 mol%
[34] or higher. Furthermore, no additives are required for the catalyst
system.
As investigated by GC and NMR, the crude reaction mixtures of the
catalytic experiments in Table 1 did not show any signs for rearranged
propargylic alcohol starting materials or products derived from them.
However, when the propargylic alcohol 1,1-diphenylprop-2-yn-1-ol
(8) was employed as substrate in combination with n-butanol, only
very small amounts of the etherification product were observed
by NMR. Instead, 1,1-diphenylethylene (9, Scheme 2) was obtained
in 74% isolated yield after column chromatography. The formation of
1,1-diphenylethylene 9 can be rationalized when assuming that the re-
action proceeds through an allenylidene intermediate (10, Scheme 2).
Allenylidene 10 can be attacked by water that had formed through
allenylidene formation, leading to 1,1-diphenylethylene (9) and a
ruthenium carbonyl complex. Such reactivity has been observed previ-
ously by us [26] and others [35]. Benzophenone, which can also be
formed as a result of the reaction in Scheme 2 [35], was observed in
the reaction mixture as well, as assessed by GC/MS (chromatogram
see supporting information). However, workup only resulted in the iso-
lation of 1,1-diphenylethylene. It appears that the diphenyl allenylidene
intermediate 10 is prone to the attack of water (or the formation of 1,1-
diphenylethylene is especially favorable), whereas the other propargylic
alcohols employed in Table 1 react with the alcohol substrates to give
the corresponding propargylic ethers.
However, the results in Scheme 2 and Table 2 do not allow for estab-
lishing a mechanism for the reaction. For the reactions in Table 1, virtu-
ally no optical rotation for the products was observed. Consequently,
other mechanisms (e.g. through carbocation intermediates) might
apply as well, and further investigations are necessary to obtain
information about the catalytically active species and to establish a
mechanism for the title reaction.
In conclusion, we demonstrated the catalytic activity of a cationic,
chiral-at-metal ruthenium allenylidene complex RRuRax−[Ru(indenyl)
L(PPh3)_C_C_CPh2]+PF6 for the etherification of secondary and
tertiary propargylic alcohols to obtain the corresponding propargylic
ethers in 9 to 73% isolated yields (1.1 mol% catalyst loading, 18 h at
100 °C in toluene). Preliminary investigations related to the mech-
anism and the identity of the catalytically active species revealed
that the reaction proceeds through an induction period and that
Scheme 3. NMR experiment to determine catalytic activity after heating the catalyst.

48
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Acknowledgment
The National Science Foundation (NSF CHE-1300818) is gratefully
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Appendix A. Supplementary data
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Supplementary data to this article (experimental details, 1H and 13
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{1H} NMR spectra of the catalysis products in Table 1 and Scheme 2,
a representative GC chromatogram and the 31P{1H} NMR spectrum
associated with 2) can be found online at http://dx.doi.org/10.1016/
j.catcom.2014.01.002.
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