Development of solid-supported Glaser-Hay couplings

Article abstract of DOI:10.1021/co500018k

While the Glaser-Hay coupling of terminal alkynes is a useful reaction, several issues associated with chemoselectivity preclude its widespread application in synthetic chemistry. To address these issues, a solid-supported Glaser-Hay methodology was developed to afford only asymmetric diyne products. This methodology was then applied to a series of immobilized alkynes with a diverse set of soluble alkynes to generate an array of heterocoupled products in high yields and purities.

Full text of DOI:10.1021/co500018k

Letter
pubs.acs.org/acscombsci
Development of Solid-Supported Glaser−Hay Couplings
Valerie T. Tripp, Jessica S. Lampkowski, Ryan Tyler, and Douglas D. Young*
Department of Chemistry, College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States
S
* Supporting Information
ABSTRACT: While the Glaser−Hay coupling of terminal
alkynes is a useful reaction, several issues associated with
chemoselectivity preclude its widespread application in
synthetic chemistry. To address these issues, a solid-supported
Glaser−Hay methodology was developed to afford only
asymmetric diyne products. This methodology was then
applied to a series of immobilized alkynes with a diverse set
of soluble alkynes to generate an array of heterocoupled
products in high yields and purities.
KEYWORDS: solid-phase synthesis, Glaser−Hay coupling, chemoselectivity, polyynes
Scheme 1. Chemoselectivity Issues Associated with the
cetylenic scaffolds, or diynes, are observed as core structures
Glaser−Hay Coupling
A
in various natural products, many polymers, and other
supramolecular materials.1−3 To date, over one thousand
naturally occurring polyynes have been isolated and found to
exhibit a range of biological activities; including antifungal,
anticancer, anti-HIV, and antibacterial properties.3 Within
polymer structures, acetylenic cores provide a versatile linear
structural moiety, giving rise to unique optical properties. For
example, when coupled with transition metals, these organo-
metallic materials display various novel properties, such as
luminescence, conductivity, and photovoltaic behavior.2 Glaser
first described the synthesis of the unique polyyne core structure
in 1869, after the oxidative dimerization of copper(I) phenyl-
acetylide upon exposure to air.4 Because of the functional group
tolerance and wide availability of acytelinic precursors, this
reaction is optimal for combinatorial chemistry, potentially
yielding large libraries of polyynes. Various modifications and
enhancements have been developed to optimize the traditional
Glaser coupling.5 One such variant developed by Hay, requires
dissolving catalytic amounts of copper(I) chloride in the
presence of bidentate tetramethylenediamine (TMEDA) and
oxygen; forming the reactive intermediate in situ, and thereby
drastically decreasing the reaction time and improving yield.6
Known as the Glaser−Hay coupling, this reaction provides an
efficient procedure for generating symmetric diyne compounds
in relatively high yields. However, one major drawback of these
reaction conditions is the lack of chemoselectivity with regards to
asymmetric coupling. When two different terminal alkynes are
coupled by a Glaser−Hay reaction, three potential polyyne
compounds are generated (Scheme 1). As a result, further
purification steps are required in order to isolate the desired
asymmetric dimer, and yields are often low because of the
formation of multiple products. While asymmetric conditions
have previously been reported in relatively high yields with either
a Cu(OAc)2 or NiCl2 catalyst system, substrate scope is limited
to alkynes that afford diynes that are isolable from homodi-
merized product. Moreover, excess of one alkyne is required and
significant purification is necessary to remove both excess diyne
and undesirable homocoupled product.7
To specifically address the problem of chemoselectivity for
heterocouplings, one of the terminal alkynes can be immobilized
on a polystyrene solid support.8 After immobilization, the
standard Glaser−Hay conditions can be utilized with higher
levels of chemoselectivity, yielding a specific heterodimer.
Furthermore, the incorporation of a solid support eliminates
the need for tedious separations and workups. A similar approach
has been taken with the Cadiot−Chodkiewicz reaction,9 which
relies on a terminal alkyne and a haloalkyne to achieve
chemoselectivity. The rigidity and pseudo-high dilution
conditions offered by the solid support eliminated the self-
coupling that was typically observed with the corresponding
solution phase Cadiot−Chodkiewicz reactions.10 By immobiliz-
ing the haloalkyne partner, the reaction proceeded in higher yield
without the generation of undesired homocoupled products.
Received: January 31, 2014
Revised: March 6, 2014
Published: March 18, 2014
© 2014 American Chemical Society
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Letter
Applying this approach to the Glaser−Hay reaction is even more
advantageous as there is no requisite for a haloalkyne to aid in the
directing of chemoselectivity, and asymmetric diynes can be
accessed directly from terminal alkyne precursors. One previous
Glaser−Hay coupling has been attempted on the solid support;
however, its aim was to provide homocoupling of the
immobilized alkyne, and not to address chemoselectivity issues.11
Because of the abundance of Glaser−Hay reaction conditions
present in the literature, reaction conditions were examined in
solution prior to optimization on the solid support. Homocou-
pling of phenylacetylene (6) was performed with different
catalytic systems based on literature precedence.12 The most
promising catalyst systems included CuCl/TMEDA, CuI/
TMEDA, and CuI/DIEPA/N-bromosuccinimide, and all were
examined toward the solution phase Glaser−Hay coupling of 6.
Overall, the CuI/TMEDA catalyst (12 h, rt) led to the highest
yields of the phenylacetylene homodimer, and was employed in
further couplings.
especially unfortunate, as they negatively impact the yield of
desired product and require further purification steps. This is
especially problematic as the use of the solid support in these
coupling reactions was intended to eliminate both of these issues.
As such, we sought to further optimize the reaction conditions to
successfully drive the reaction to completion without the
production of the homodimer impurities.
It was speculated that decreasing the initial loading of 2 on the
solid support could efficiently prevent the undesirable
dimerization on the functionalized resin. Our initial preparation
of 1 consisted of swelling the resin in CH2Cl2 for 15 min,
followed by the addition of propargyl alcohol (10 equiv) and
triethylamine (10 equiv). The reaction was stirred for 16 h at
room temperature to achieve maximum loading of the starting
material. After the discovery of the cross-linked homodimer
product, we attempted to generate lower loaded resins by
decreasing the amount of reagents and immobilization time
employed in the immobilization protocol.
With optimized solution-phase conditions established, we
transitioned the optimization to the solid support. In order to
assess the feasibility of the approach, various immobilization
strategies of propargyl alcohol (2) were investigated with
carboxy, trityl chloride, and bromo Wang resins; however,
ultimately a trityl chloride derivatized resin was selected because
of the mild immobilization/cleavage conditions and the
reproducibility of propargyl alcohol loading. Initially 2 (10
equiv) was reacted at room temperature with trityl choloride
resin in the presence of triethylamine (10 equiv) for 16 h to
afford propargyl alcohol immobilized resin (1). The coupling
conditions were then optimized via the reaction of 1 with
phenylacetylene (6), varying solvent, temperature, and resin
loading.
Because of the hydrophobic nature of the polystyrene core,
solvent selection is important to reaction optimization due to the
resin’s propensity to swell or contract as a result of solvent
polarity. Consequently, we investigated toluene, THF, DCM,
and acetonitrile as viable solvents for the solid-supported
reaction. Overall, THF consistently generated the highest yields
of coupled alkyne products, while significant amounts of
unreacted 2 remained in other solvents after 12 h at room
temperature.
While THF afforded the highest yields, some starting material
still remained, indicating the necessity for further optimization.
Consequently, temperature was varied, to elucidate optimal
conditions. A range of temperatures was examined, including 30,
60, and 80 °C, with the 60 °C conditions yielding the most
promising results. The reactions at 30 °C still contained
unreacted starting material, indicating that the temperature was
not sufficient to drive the reaction to completion. Meanwhile, the
reactions stirred at 80 °C demonstrated complete conversion,
but afforded lower yields. This noticeable decrease in the
formation of diyne product most likely resulted from the
overheating and destruction of some of the polystyrene resin.
Some of the copper catalyst was also found to decompose within
the reaction vessel, suggesting that the temperature may
inactivate the catalyst, thereby reducing the efficiency of the
reaction. Reaction of 1 with 6 for 12 h at 60 °C afforded the ideal
conditions for virtually quantitative conversion of propargyl
alcohol precursor.
To assess the effects of resin loading on the reaction, several
resins were prepared. Trityl chloride resin was again reacted with
10 equiv of propargyl alcohol in the presence of 10 equiv of
triethylamine. The reaction was then stirred at 40 °C for 16 h,
with the aim of achieving a higher loaded resin, ∼1.8 mmol/g. An
identical reaction was set up but heated to 40 °C for only 2 h to
generate a medium loaded resin, ∼1.0 mmol/g. Additionally, the
amount of propargyl alcohol was decresed to afford even lower
loaded resin ∼0.6 mmol/g. Similar immobilizations were also
performed on a 2% DVB cross-linked resins to afford similarly
loaded resins that provided an increased degree of resin rigidity
to discourage interactions of immobilized alkynes. After a
sufficient work up, a portion of each version of the resin was
cleaved in 2% TFA and analysis of loading by GC/MS and mass
recovery of propargyl alcohol.
The resins were then subjected to coupling conditions with 6
at 60 °C for 16 h. The level of cross-linked DVB within the resin,
1% or 2%, showed little effect on the suppression of homodimer.
This result indicates that the concentration of loading plays a
larger role in the formation of homodimer than resin rigidity.
After the necessary work up conditions, it was established that
resin loaded above 0.7 mmol/g of propargyl alcohol forms
undesired homodimer during the reaction conditions. Resin
loaded at a concentration less than 0.7 mmol/g successfully
eliminates homodimer formation while still generating desired
heterocoupled products.
Having elucidated optimized solid-supported Glaser−Hay
conditions, the scope of the methodology was assessed via the
preparation of a diverse library of diynes. Toward this end, two
additional alkynes, 3 and 4, were immobilized on the trityl-
chloride resin at loadings of ∼0.6 mmol/g. These were then
reacted in THF with a CuI/TMEDA catalyst and a diverse set of
soluble alkynes to assemble a small library of conjugated diynes.
After 16 h of stirring at 60 °C, the resin reaction was filtered then
washed with alternating volumes of CH2Cl2 and MeOH to
remove unreacted reagents and other impurities. The resin was
then cleaved with 2% TFA, the solvent was removed in vacuo,
1
and the product was analyzed by TLC, H NMR, and GC/MS
(Table 1).
The solid supported Glaser−Hay coupling tolerated a variety
of functionalities, including aromatic rings, silyl groups, free
amines, alcohols, and alkyl chains. Moreover, the reaction with
both 5 and 6 was scaled up 10-fold (500 mg of resin) with
comparable yields, suggesting that larger quantities of product
could be obtained if desired. Reactions not proceeding to
Upon further investigation, it was discovered that despite
complete conversion, there was also dimerization of the
immobilized alkyne, to afford an undesired homodimer product
(12). The occurrence of the starting material and homodimer are
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Letter
similar benzyl alcohol, 3, had relatively lower yields. Moreover,
the 3-ethynylthiophene reactant, 8, also afforded lower yields
likely due interaction with the copper catalyst.
Table 1. Glaser−Hay Couplings with Immobilized Propargyl
Alcohol
Utilizing a propargyl amine derivatized resin, 21, with the
optimized coupling conditions we expanded the diyne library
(Table 2). Less homodimer formation was observed with this
Table 2. Glaser−Hay Couplings with Immobilized Propargyl
Amine
completion under these conditions were quickly purified from
starting material via a silica plug. While the reaction conditions
were favorable for most alkynes, alkynes containing nucleophilic
residues, such as 2, 3, 4, 8, and 11, often resulted in lower yields.
To alleviate this, a trityl-protected version, 7, was employed and
gave significantly higher yields of the desired product than the
unprotected amine 4. Conveniently, the 2% TFA cleavage
conditions also removed the trityl protecting group on the amine,
thereby yielding the same product as reaction with the free
amine. We hypothesize that the free amine functionality may
have coordinated with the copper catalyst, reducing its activity
within the reaction. This trend continued when analyzing the
yields associated with other nucleophilic moieties. While the
anisole-based 9 reacted well under the idealized conditions, the
resin, even at higher loadings (0.9 mmol/g), indicating a lower
reactivity than that observed with propargyl alcohol loaded resin.
The library was further expanded via the immobilization and
reaction of 3 to yield 30 at loadings of 0.7 mmol/g. This resin
exhibited similar reactivity as the propargyl alcohol immobilized
resin (Table 3).
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Letter
Table 3. Glaser−Hay Couplings with Immobilized
Ethynylbenzyl Alcohol
ASSOCIATED CONTENT
* Supporting Information
Experimental protocols and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: dyoung01@wm.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank the Jeffress Memorial Trust and the
College of William & Mary for financial support of the research.
■
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Overall, a novel methodology has been developed that affords
a direct route to asymmetrical diynes, solving chemoselectivity
issues. The solid-supported Glaser−Hay reaction tolerates a wide
range of chemical functionalities and has afforded the
construction of a small library of asymmetric diynes. It is
important to note, however, that careful attention must be paid
to the loading of immobilized alkyne in order to prevent
undesired homodimerization. With the optimized conditions in
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