Rapid and efficient desilylation and deuteration of alkynylpyridines

Article abstract of DOI:10.1016/j.tetlet.2015.05.063

We describe a rapid and efficient technique for the direct installation of deuterium atoms following the removal of trimethylsilyl groups from alkynylpyridines. Utilizing tetrabutylammonium fluoride in the presence of deuterium oxide, we observe up to 97% deuterium incorporation in as little as one minute of reaction time.

Full text of DOI:10.1016/j.tetlet.2015.05.063

Tetrahedron Letters 56 (2015) 4232–4233
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Tetrahedron Letters
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Rapid and efficient desilylation and deuteration of alkynylpyridines
⇑
Benjamin S. Gelinas, Joseph A. Jaye, Gabriela R. Mattos, Eric H. Fort
Department of Chemistry, University of St. Thomas, 2115 Summit Ave., St. Paul, MN 55105, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a rapid and efficient technique for the direct installation of deuterium atoms following the
removal of trimethylsilyl groups from alkynylpyridines. Utilizing tetrabutylammonium fluoride in the
presence of deuterium oxide, we observe up to 97% deuterium incorporation in as little as one minute
of reaction time.
Received 2 April 2015
Revised 14 May 2015
Accepted 18 May 2015
Available online 21 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Alkynylpyridine
Isotopic labeling
Desilylation
Deuteration
Introduction
were able to achieve very high deuterium incorporation in as little
as one minute of reaction time; though, conventional heating is
Palladium catalyzed cross-coupling of terminal alkynes has
become a common method for installing ethynyl groups. Often
trimethylsilylacetylene (TMSA) is used as a coupling partner due
to the ease of desilylation to produce a new terminal alkyne.
These alkynes can then be used on their own merit or for further
also effective. Herein, we describe this rapid and efficient one-pot
reaction for removing trimethylsilyl groups from alkynylpyridines
and directly installing deuterium atoms. Three previously
unknown deuterated alkynylpyridines are also reported.
1
coupling. Isotopically labeled structures of this kind are required
Results and discussion
for mechanistic and kinetic studies.2 New methods for deuterium
enrichment are vital to broadening the availability of molecules
used in these experiments.
–4
The alkynes used for the previous techniques are often formed
from Sonogashira cross coupling of TMSA followed by desilyla-
1
a,b
Though successful methods of incorporating deuterium have
tion.
In the case of desilylation, methods often include a
5
,6
been shown on various silylated allyl, vinyl, and aryl substrates,
nucleophile to remove the silyl group and the resulting
carbanion then scavenges a proton from the surrounding solvent
or reagents. We hypothesized that deuterium could be installed
directly in this process following desilylation. Precedent
suggested carbonate and tetrabutylammonium fluoride (TBAF)
traditional methods for installing deuterium on terminal alkynes
often involve deprotonation with strong bases followed by deuter-
2
,3
ation. These methods are often lengthy and require slow addi-
tion of the base at low temperatures. Only recently have milder
conditions become available, though they still follow this general
9
would be the best suited nucleophiles. These reagents were
7
synthetic approach. In addition, generally accepted techniques
screened with 2,6-bis(TMS-ethynyl)pyridine (1) to produce 2,6-
di(ethynyl-d)pyridine (2) in the presence of the following deuter-
ated compounds: methanol, water, trifluoroacetic acid, and ammo-
nium chloride. We analyzed these results and the others in this
article by comparing the integration of aromatic signals with those
for desilylation are not commonly conducive to achieving high
deuterium incorporation or often take hours of reaction time for
6,8
high levels of deuterium incorporation. A versatile and fast tech-
nique for the direct deuteration of silyl-protected alkynes could
shorten the pathway to these valuable materials.
1
of residual terminal C–H signal in the H NMR Spectrum.
As part of an ongoing research project, we required terminal
deuteration of alkynylpyridines. As a result, we screened condi-
tions in an effort to both desilylate and incorporate deuterium in
a one-pot reaction. With the inclusion of microwave heating, we
Literature procedures for the protonation with trifluoroacetic
acid and ammonium chloride typically involve a quench following
desilylation. We followed these protocols for our initial screen. All
of these reactions proved successful in incorporating deuterium
2
into the final product, yet 110 equiv of D O and 2.5 equiv TBAF
⇑
Corresponding author. Tel.: +1 651 962 5588; fax: +1 651 962 5201.
E-mail address: ehfort@stthomas.edu (E.H. Fort).
was most effective, providing 90% yield with 79% deuterium incor-
poration to 1. We then screened all of the deuterated solvents with
http://dx.doi.org/10.1016/j.tetlet.2015.05.063
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0

B. S. Gelinas et al. / Tetrahedron Letters 56 (2015) 4232–4233
4233
the same concentrations using both K
2
CO
3
and TBAF in THF. We
that in 2 min, each molecule could be deuterated to near
complete isotopic incorporation in reasonably high yield. 2,5-
Bis(TMS-ethynyl)pyridine (3), 2-(TMS-ethynyl)pyridine (4), and
3-(TMS-ethynyl)-pyridine (5) were quickly converted to 2,5-
di(ethynyl-d)pyridine (6), 2-(ethynyl-d)pyridine (7), and 3-(ethy-
nyl-d)pyridine (8), and all incorporated deuterium in greater than
90%. The mono-ethynylpyridine derivatives required more reaction
time to give better results primarily due to the difficulty in drying
the liquid reagents as thoroughly as the solid diethynylpyridine
compounds. At one minute, all of the pyridine molecules are fully
desilylated, but deuterium incorporation suffers. The synthesis of
2-(ethynyl-d)pyridine has been previously reported from the
deprotonation and deuteration of 2-ethynylpyridine with triethy-
found that TBAF with either D O or CD
2
3
OD was the most effective.
The deuterated methanol had slightly better yields but lower deu-
terium incorporation. A summary of these results can be found in
1
0
Table S1.
It is likely that the low deuterium incorporation for many of the
initial reactions arises from the hygroscopic nature of the reagents.
The use of carbonate, one of the most popular reagents for desily-
lation, often resulted in a significant incorporation of protons
despite extensive drying of the reagent prior to use.10 Potassium
fluoride also had this problem, as did methods using silica and alu-
mina (trials not shown).11 It should be noted that commercially
available tetrabutylammonium fluoride (TBAF) solutions often
contain up to 5% water, but these could be effectively dried over
molecular sieves prior to use. Acetone was extremely wet and
served as a proton donor. Though the reaction worked in ether
and dichloromethane, tetrahydrofuran allowed convenient access
1
4,15
lamine, similar to the procedure by Sajiki.
Molecules 6, 7,
and 8 are new to the literature.
Conclusions
2
to elevated temperatures in the microwave. Since D O incorpo-
rated deuterium to a greater extent than any of the other deuter-
ated solvents and is more cost effective, we decided to optimize
We report the efficient one-pot synthesis of several isotopically
enriched ethynylpyridines by direct desilylation and subsequent
deuteration of TMS-ethynyl pyridines. After screening common
desilylation techniques, we found tetrabutyl ammonium fluoride
in the presence of deuterium oxide was able to incorporate deu-
terium in greater than 90% under both conventional thermal heat-
ing and microwave conditions. This approach is a fast and
convenient method for installing deuterium following cross-
coupling reactions and can readily prepare isotopically labeled pre-
cursors for mechanistic studies.
the reaction further with D
We optimized the reaction conditions for the production of 1
with THF, D O, and TBAF, screening deuterium source and equiva-
2
O.
2
lents, heat source, nucleophile source and equivalents, time, and
temperature (Table S2).10 It was found that the best deuterium
incorporation into the products occurred with a 0.08 M solution
1
2
of pyridine derivative and 0.2 equiv of TBAF per silyl group.
Concentrating the reactions any further resulted in diminished iso-
topic yields. Both microwave and conventional heating were effec-
tive at converting 1 to 2 in high yields and high deuterium
incorporation in less than two minutes at reaction temperature.
Any decrease in reaction time from the microwave seemed to
be from the rapid heating on these short time scales. When com-
paring heat up and cool down times on the microwave, the total
reaction time was between two and three minutes. Pulsed power
and constant wattage experiments were run, but again, no benefit
was gained primarily due to the extremely short reaction time and
the observation that pulsed power methods benefit reactions with
Acknowledgements
We would like to thank the University of St. Thomas and the
Donors of the American Chemical Society Petroleum Research
Fund for support of this research. This work was also supported
in part by the National Science Foundation through the University
of Minnesota MRSEC under Award Number DMR-0819885.
Supplementary data
1
3
low absorbing solvents and highly absorbing reagents. In our
case, THF and D O are both exceptional solvents for absorbing
2
Supplementary data (procedures for the cross-coupling reaction
to produce TMS-ethynylpyridines, desilylation reactions, and spec-
tra for molecules 1–8) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
microwave radiation.
Since microwave reactors are often limited in scale, we also per-
formed the reaction of 1 to 2 on a tenfold scale using conventional
thermal heating and still achieved 89% deuterium incorporation
with yields of 86% in less than 50 min. We applied the optimized
conditions for the conversion of 2,6-bis-(TMS-ethynyl)-pyridine
0
63. These data include MOL files and InChiKeys of the most
important compounds described in this article.
(
1) into 2,6-di (ethynyl-d)pyridine (2) to a series of three additional
References and notes
trimethyl silyl protected ethynyl pyridines (Table 1). We found
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: R ,R = TMS-ethyne; R ,R = H
: R ,R = TMS-ethyne; R ,R = H
: R = TMS-ethyne; R ,R ,R = H
: R = TMS-ethyne; R ,R ,R = H
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=
=
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% Da
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3
4
5
90
90
90
90
1
1
2
2
90
79
82
66
96
97
90
92
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7
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1
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a
All reported values are averages of a minimum of three runs.