Synthesis of triphenylsilyl[14C2]acetylene for use in a Sonogashira reaction

Article abstract of DOI:10.1002/jlcr.1808

Silylacetylenes are useful coupling partners for aromatic halides in the Sonogashira reaction and a C-14 labeled version of this useful synthon would allow ready access to a wide variety of arylalkynes. Ca¹⁴C ₂ was converted to triph

Full text of DOI:10.1002/jlcr.1808

Research Article
Received 13 April 2010,
Revised 2 June 2010,
Accepted 3 June 2010
Published online 5 August 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1808
Synthesis of triphenylsilyl[14C2]acetylene
for use in a Sonogashira reaction
Ã
Charles S. Elmore, and Peter N. Dorff
Silylacetylenes are useful coupling partners for aromatic halides in the Sonogashira reaction and a C-14 labeled version of
this useful synthon would allow ready access to
a
wide variety of arylalkynes. Ca14C2 was converted to
triphenylsilyl[14C2]acetylene using two related routes in 65% yield, and the resulting [14C2]acetylene was coupled with
an aryl halide to give the target triphenylsilylarylacetylene (2) in 40% yield.
Keywords: triphenylsilylacetylene; calcium carbide; Songashira reaction
activity of the material, and they gave a specific activity of 15 mCi/
mg. There was considerable variation in the specific activity
measurements (12–23 mCi/mg) due to the heterogeneity of the
material. The radioactive portion of the calcium carbide had a
specific activity of 117 mCi/mmol. All other reagents were
obtained from Aldrich or Acros and were used without purifica-
tion. 1H NMR spectra were recorded in CDCl3 on a Bruker Avance
500 and were referenced to the residual solvent peak (7.26).
Preparative HPLC purifications were performed using a 250Â 21.2-
mm Phenomenex Luna C-18(2) column and MeCN-0.1% Formic
acid as the eluent. Analytical HPLC analyses were performed using
an Agilent 1100 series HPLC system on a Phenomenex Luna C-
18(2) column using a gradient of 50–100% MeCN-0.1% TFA over
10 min followed by a 5-min wash with 100% MeCN.
Introduction
Carbon–carbon triple bonds are important structural motifs in
organic chemistry. They can be found in drug and drug candidate
molecules, such as ethinylestradiol and mGluR5 receptor antago-
nists,1,2 and enediyne antibiotics, such as Neocarzinostatin,3 and
they provide ready access to numerous other functional groups
via well-precedented transformations. The synthetic accessibility
of aryl alkynes was dramatically improved with the report of what
has come to be known as the Sonogashira reaction in 1975.4 This
reaction involves the Pd-catalyzed coupling of a monosubstituted
alkyne with an aryl or alkenyl halide or triflate.4–6
Many different Pd-containing catalysts have been demon-
strated to catalyze the reaction; these catalysts can be divided
into two broad classes of ligated and ligand free. Ligated
catalysts vary considerably; Pd(PPh3)4, palladacycles, and N-
heterocyclic carbene containing Pd catalysts have shown good
efficacy in catalyzing the coupling. Traditionally, the Sonogashira
reaction uses a copper(I) co-catalyst to generate the copper
alkyne which then undergoes transmetalation to give the
palladium alkyne. These conditions can lead to byproduct
formation (dimerizeration) via the Glaser coupling that occurs
under very similar reaction conditions.7 Dimerization can be
reduced by slow addition of the alkyne to the reaction mixture8
and by running the reaction under a H2 atmosphere.9 There
have also been numerous reports of copper-free conditions that
completely eliminate the need for a copper co-catalyst.10–12
Despite the utility of this chemistry, there are few reports in
the literature of the use of C-13 or C-14 labeled acetylenes
in Sonogashira reactions.13 This is due, in part, to the difficulty in
preparing the requisite alkyne and to the low yields inherent in
the Sonogashira when the alkyne is used as the limiting reagent.
Triphenylsilyl[14C2]acetylene: Route A
A two-necked, round-bottomed flask containing 775 mg (approx
15 mCi/mg, 12 mCi, 0.10 mmol) of Ca14C2 was fitted with a
septum and was connected to a vacuum manifold through a gas
drying tube containing drierite. The other port on the manifold
was connected to a two-necked, round-bottomed flask that had
a septum in one port and a drying tube containing K2CO3
connected to the gas manifold in the other. The apparatus was
evacuated and the valve leading to the vacuum closed. Water
(2.5 ml) was added to the Ca14C2 through the septum and the
resulting slurry was stirred at rt. While the water was being
added, the other flask was cooled in liquid nitrogen to trap the
resulting gases. After 5 min of condensing [14C2]acetylene, the
valve connecting the flask to the manifold was closed. A solution
of 3 ml of 3 M EtMgBr in Et2O and 4 ml of THF (under a N2
atmosphere) was added via cannula to the cold acetylene and
the solution was stirred for 30 min at 01C and then at room
Experimental
Isotope Chemistry, CNS Chemistry, AstraZeneca Pharmaceuticals LP, Wilmington,
DE 19850, USA
General
Ca14C2 was obtained from American Radiolabeled Chemical
Company and contained considerable non-radioactive impurities.
*Correspondence to: Charles S. Elmore, 911 Barley Ct., Landenberg, PA 19350,
USA.
Multiple analyses were performed to determine the specific E-mail: chad_elmore@yahoo.com
J. Label Compd. Radiopharm 2011, 54 51–53
Copyright r 2010 John Wiley & Sons, Ltd.

C. S. Elmore and P. N. Dorff
temperature for 1 h. A solution of 2.01 g (6.83 mmol) of H2 atmosphere was stirred for 20 min and then 85 ml (0.61 mmol)
triphenylchlorosilane in 4 ml of THF was added and the solution of NEt3 was added and the solution was warmed to 80 C.
was stirred overnight under N2. The reaction was diluted with A carefully degassed solution of 4.3 mCi (0.038 mmol, 11 mg)
20 ml of water and was extracted four times with 20 ml of Et2O. triphenylsilyl[14C2]acetylene in 1 ml of MeCN was added drop-
The combined organic layers were washed twice with 25 ml of wise over 20 min. The solution was heated at 801C for 1.5 h and
brine and 25 ml of H2O and was dried (MgSO4). Filtration was then concentrated to dryness under a stream of nitrogen.
followed by concentration gave 9.2 mCi of triphenylsilyl[14C2]- Purification by preparative HPLC (75–100% over 5 min then hold
acetylene (radiochemical purity 94%), which was purified by at 100% MeCN for 10 min) afforded 1.84 mCi of Isoindolone 1
silica gel chromatography (100% hexane) to give 7.7 mCi (43%, 498% radiochemical purity with a specific activity of
1
(radiochemical purity 498%). H NMR (500 MHz, CDCl3) d ppm 117 mCi/mmol).
2.78 (s, 1 H), 7.38 (m, 9H), 7.66 ( d, J = 6.71 Hz, 6 H).
Results and discussion
Route B
Isoindolone 1 was required labeled with C-14 in a metabolically
A solution of 64 mg (0.12 mmol, 13.4 mCi) of 1,2-bis(triphenylsi-
lyl)[14C2]acetylene in 20 ml of THF and 200 ml of MeOH was
stirred as 50 ml (50 mmol) of 1 M n-Bu4NF in THF was added. The
solution was stirred rapidly for 20 min at room temperature and
was then passed through a light silica Sep-Paks cartridge, which
was subsequently washed with 10 ml of THF. The volatiles were
removed and the residue was purified by preparative HPLC
(50–100% over 10 min then hold for 10 min) to give 11.4 mCi
(29 mg, 498% radiochemical purity) of triphenylsilyl[14C2]acetylene.
stable position for use as a synthetic intermediate. Although it is
possible to incorporate the C-14 label into the isoindolone ring
of 2 via the medicinal chemistry approach, the synthesis would
have been quite long and low yielding.14 The next step in the
medicinal chemistry synthesis afforded the opportunity to
incorporate C-14 via a Sonogashira reaction. This had the
advantage of late-stage incorporation of radioactivity while
avoiding some of the difficult, low-yielding steps found in the
preparation of 2 (Scheme 1). However, to the best of our
knowledge, a Sonogashira reaction using a C-14 labeled
acetylene has not been reported previously although it
has been conducted on an acetylene containing a S-35 labeled
side chain.15
1,2-Bis(triphenylsilyl)[14C2]acetylene
[14C2]Acetylene was generated as was described in route A for
the generation of triphenylsilyl[14C2]acetylene using 962 mg
(15mCi/mg, 14 mCi) of Ca14C2 and 2.9ml of water. To the two-
necked receiving flask was added a solution of 2.4ml of 1.6M
(3.8mmol) n-BuLi in hexane in 15ml of THF through the sidearm.
The reaction vessel was then warmed to À781C and was stirred
for 25 min. A solution of 1.12 g (3.80 mmol) of triphenylchlorosi-
lane in 6 ml of tetrahydrofuran was added, and the solution was
stirred at À781C for 30 min, at 01C for 3h, and then at room
temperature overnight. The reaction mixture was diluted with
30 ml of water and was extracted four times with 30 ml of Et2O.
The combined organic layers were washed three times with 20 ml
of water and then dried (MgSO4). After filtering, the solvent was
removed and the residue was taken up in 10ml of MeCN. The
solution was cooled at 01C for 1h and was then filtered. The
filtrate was then purified by preparative HPLC (50 to 100% over
20 min) in three batches to give 10.6mCi as a yellow solid. 1H NMR
(500 MHz, CDCl3) d ppm 7.40 (m, 18 H) 7.69 (d, J = 6.7 Hz, 12H).
The medicinal chemistry route utilized trimethylsilylacetylene
as a coupling partner in the Sonogashira reaction. This reagent is
not readily available in C-14 labeled form; hence, we decided to
To vacuum
Valves
K2CO3 packed
drying tube
Drierite packed
drying tube
Isoindolone 1
A mixture of 0.19 mmol of 2, 0.44mg (2.3mmol) of CuI, and 5.37 mg
(7.65 mmol) of dichlorobis(triphenylphosphine)palladium(II) under a
Figure 1. Apparatus for generating [14C2]acetylene and reacting it with BuLi or
EtMgBr.
R
O
R
O
N
R'
Ca14C2
Br
N
R'
14C
14C
Ph3Si
2
14CH
14C
Ph3Si
Ph
Si
Ph
Ph
1
14C
Ph 14C
Si
Ph
Ph
Scheme 1. Retrosynthetic analysis for isoindolone 1.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 51–53

C. S. Elmore and P. N. Dorff
R
O
R
O
N
R'
N
R'
EtMgBr, THF
Ph3SiCl
65%
Br
14CH
14C
2
14C
14C
Ph3Si
Ca14C2
Ph3Si
CuI, NEt3 MeCN,
Pd(PPh3)2Cl2, H2
1
40%
SiPh3
n-Bu4NF,
THF
14C
14C
14C
14C
Ph3Si
85%
n-BuLi, THF
Ph3SiCl
75%
SiPh3
14C
14C
Ph3Si
Scheme 2. Synthesis of isoindolone 1 from Ca14C2.
prepare it from C-14 acetylene; however, after verifying that was not removed during silica gel chromatography interfered
triphenylsilylacetylene (TPSA) was also an effective coupling with the reaction. The use of MeCN as solvent gave a higher
partner, it was decided to target that alkyne instead to reduce yield than the use of a amine solvent such as diisopropylamine.
the volatility of the C-14-labeled intermediate.
Slow addition of the alkyne to the reaction mixture and the use
Two approaches to the preparation of [14C2]TPSA were of a H2 atmosphere in place of argon dramatically reduced the
investigated: (1) a one-step deprotonation–alkylation approach amount of homocoupling. However, the reaction yield was still
and (2) a two-step deprotonation bis-alkylation, deprotection highly variable (from 15% to 75% with 40% being the norm) and
approach. These approaches are depicted in Scheme 1. In both so the Sonogashira reaction was conducted multiple times in
the approaches, addition of water to Ca14C2 produces acetylene small batches and the products combined to mitigate the loss in
gas, which is transferred via a vacuum manifold to a reaction case a reaction gave a poor yield. No reduction of the triple
flask using standard vacuum transfer methodology (Figure 1).16 bond to give alkene or alkane products was observed by LC/MS
The [14C2]acetylene gas was passed through a column contain- although if this reduction occurred prior to the Sonogashira
ing CaCO3 and then through a column containing K2CO3 to dry coupling, it likely would not have been observed.
it prior to anion formation.
For the direct, one-step approach, a solution of ethylmagne-
sium bromide was added to the condensed acetylene and the
solution was then warmed to 01C (Scheme 2).17 After complete
anion formation, a solution of triphenylsilyl chloride was
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