Copper-free palladium-catalyzed sonogashira-type coupling of aryl halides and 1-aryl-2-(trimethylsilyl)acetylenes

Article abstract of DOI:10.1016/j.tet.2005.01.032

A one-pot procedure for the direct coupling of 1-aryl-2- trimethylsilylacetylenes with aryl halides to give diaryl acetylenes is reported. The procedure does not involve the use of copper(I) iodide. Improvement in reaction yields has been obtained by replacing conventional oil bath heating with the use of microwave dielectric heating.

Full text of DOI:10.1016/j.tet.2005.01.032

Tetrahedron 61 (2005) 2697–2703
Copper-free palladium-catalyzed sonogashira-type coupling of
aryl halides and 1-aryl-2-(trimethylsilyl)acetylenes
*
Ulrik S. Sørensen and Esteban Pombo-Villar
Nervous System Research, Novartis Pharma AG, WSJ-386.7.15, Lichtstrasse 35, CH-4002 Basel, Switzerland
Received 12 November 2003; revised 7 January 2005; accepted 12 January 2005
Abstract—A one-pot procedure for the direct coupling of 1-aryl-2-trimethylsilylacetylenes with aryl halides to give diaryl acetylenes is
reported. The procedure does not involve the use of copper(I) iodide. Improvement in reaction yields has been obtained by replacing
conventional oil bath heating with the use of microwave dielectric heating.
q 2005 Published by Elsevier Ltd.
1
. Introduction
We have studied the direct coupling of trimethylsilylacetyl-
enes to give disubstituted acetylenes in a one-pot procedure
which does not require isolation of the terminal alkyne after
The palladium-catalyzed carbon–carbon bond forming
reactions developed through the last decades remain of
great value to synthetic organic chemists. One such reaction,
1
3
deprotection. It has been described that this type of
palladium-mediated coupling can be accomplished in the
1
–3
14
15
the Sonogashira coupling,
involves the preparation of
presence of equivalent or catalytic amounts of silver
ions. In another recent study, describing the copper-
palladium cocatalyzed cross-coupling of (arylethynyl)tri-
methylsilanes and aryl halides or triflates, it was concluded
that catalytic amounts of copper are required for such a
substituted acetylenes by coupling aryl or vinyl halides with
terminal acetylenes in the presence of a palladium catalyst
and copper(I) iodide as cocatalyst. Although there are
examples of Sonogashira-type couplings without the use of
4
–9
1
6
a copper cocatalyst, its use together with palladium is by
far the most common procedure. Furthermore, copper(I) in
itself is known to efficiently mediate the homo- and
coupling reaction to take place. Thus, with the omission of
copper(I) chloride in the otherwise successful reaction of
4-acetylphenyl trifluoromethanesulfonate with 1-phenyl-2-
1
0
heterocoupling of terminal acetylenes,
undesirable side-reaction in several applications of the
Sonogashira reaction.
being an
trimethylsilylacetylene these authors could not detect any
formation of the desired coupling product. In contrast to the
1
7,18
19
or stoichiometric amount of
use of an either catalytic
copper, the result of our work presented here is a procedure
for the direct coupling of trimethylsilylacetylenes to give
Numerous reports describe the coupling of trimethylsilyl-
acetylene with aryl halides in Sonogashira-type reactions.
The C(sp)–Si bond is generally not affected by these
reaction conditions. The silyl group can, therefore, if
desired, subsequently be removed to furnish a structurally
modified terminal alkyne. The trimethylsilyl group is
thereby used as a protective group, and as recently
exemplified within solid-phase synthesis, the functionalized
terminal alkyne formed by cleaving off the trimethylsilyl
functionality with for example tetrabutylammonium fluoride
1,2-diaryl acetylenes in a palladium-catalyzed reaction
without the use of a copper cocatalyst and furthermore
16
with a reduction in the reaction time from several hours to
only minutes by means of microwave heating. Regarding
19–27
2
,5
the use of microwaves,
it has recently been reported
that aryl trimethylsilylacetylenes can be prepared efficiently
from trimethylsilylacetylene and an aryl halide using
standard Sonogashira coupling conditions and microwave
28
irradiation with much reduced reaction times. Thus, as
16
recently exemplified in a one-pot procedure, combining
(TBAF) or aqueous alkali can subsequently be subjected
to reactions like the Mannich reaction or a second
Sonogashira cross-coupling step.
1
1
1
2
the introduction of the trimethylsilylethynyl functionality
and subsequent coupling with an aryl halide represents a
useful tool for the preparation of diarylacetylenes. An
example of this class of compounds which has been of great
interest to us is the neuroactive compound 2-methyl-6-
(phenylethynyl)pyridine (MPEP, 4, Table 2), found to be a
Keywords: Microwaves; Sonogashira-type coupling; 1-Aryl-2-trimethyl-
silylacetylenes; Diaryl acetylenes.
*
Corresponding author. Tel.: C416 1324 9865; fax: C416 1324 3811;
e-mail: esteban.pombo@pharma.novartis.com
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.01.032

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U. S. Sørensen, E. Pombo-Villar / Tetrahedron 61 (2005) 2697–2703
Table 1. Reaction conditions for coupling of 1-phenyl-2-(trimethylsilyl)acetylene (1) and 3-halopyridines
a
Entry
X
Method
Solvent
Catalyst
T (8C)
Base/transf.
b
cat.
Yield (%)
32
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
I
I
I
I
I
I
I
I
I
I
I
I
A
B
A
A
A
A
A
A
A
DMF
DMF
DMF
DMF
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
100
100
100
100
100
100
100
100
100
A
B
B
B
B
C
D
B
B
B
B
B
B
B
B
B
c
53
61
c
/(o–tol)
3
P
71
16
64
5
2
n-Bu O
H O/DMF 1:9
2
DMF
DMA
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
28
/(o–tol)
3
P
d
rt
10
11
12
13
14
15
16
c
B
A
A
A
A
A
100
100
140
62
c
74
58
37
87
90
e
180
Pd(PPh
3
)
2
100
100
Pd(OAc)
2
/(o–tol)
3
P
a
b
c
d
e
Method A: microwave heating, Method B: conventional heating.
A: NaOAc/Bu NBr, B: NaOAc/Bu NCl, C: K CO /Bu NCl, D: triethylamine.
Average of two determinations (see footnote ).
Reaction time 16 h.
Reaction time 4 min.
4
4
2
3
4
†
highly potent and selective antagonist for the metabotropic
2
glutamate receptor subtype mGlu5.
As can be seen from Figure 1, heating the reaction mixture
in a hot oil bath (Method B) results in much slower heating
and conversion rates, and the rapid heating when applying
microwaves may be the explanation for the higher isolated
yields obtained in the cases where comparable experiments
were carried out.
9,30
2
. Results and discussion
Initially, we studied the coupling of 1-phenyl-2-(trimethyl-
silyl)acetylene (1) with 3-bromo- or 3-iodopyridine to
identify the optimal reaction conditions (Table 1). Com-
pound 2 was isolated in a moderate 28% yield (entry 10,
Table 1) when the reaction (scale 2.50 mmol) was carried
out at room temperature overnight in the presence of
5
mol% palladium acetate together with sodium acetate and
tetrabutylammonium chloride. Performing this transform-
ation at elevated temperature applying 15 min of microwave
irradiation (Method A), resulted in an initial improvement
of the reaction to 74% isolated yield of 2 when starting from
3
†
-iodopyridine (entry 12, Table 1).
We found the reaction to be highly reproducible when using
a microwave instrument that allows for control and
monitoring of temperature as well as giving efficient
stirring. For most of our experiments DMF was used as
solvent. With its high polarity it absorbs microwaves well,
resulting in very rapid heating. Using typically 50 ml of
DMF as solvent and irradiation at 450 W, we achieved a
temperature increase from room temperature to 100 8C
within less than 30 s.
Figure 1. Experiments performed using identical scale (50 ml solvent) and
identical reaction flasks and magnetic stirring bars. Upper graph: For MW
experiment, a sensor placed in the reaction mixture allows for on-line
temperature control and monitoring. For oil bath, values are average of
three determinations (maximal deviation two degrees Celsius). Lower
graph: Conversion rates (single determination) were calculated from
H-NMR spectral data of crude product (desired product/aryl halide).
†
Isolated yields obtained in the repeated microwave experiments: 75 and
73% from 3-iodopyridine (Table 1, entry 12); 61 and 60% from 3-
bromopyridine (Table 1, entry 3). For the oil bath experiments, 60 and
6
5
4% were obtained from 3-iodopyridine (Table 1, entry 11) and 50 and
6% from 3-bromopyridine (Table 1, entry 2).

U. S. Sørensen, E. Pombo-Villar / Tetrahedron 61 (2005) 2697–2703
2699
Thus, for the synthesis of 2 an average of 74% yield from
two determinations (entry 12, Table 1) was obtained in the
former case as compared to 62% for two otherwise identical
dependent, and the coupling product was formed only in
cases where the aryl halide was sufficiently activated. As
could be expected, iodides afforded better results than the
corresponding bromides. For the benzoic acid methyl esters,
efficient conversion-rates were obtained for the 3- and
2-substituted derivatives, yielding after 15 min at 100 8C
compounds 8 and 9 in 84 and 85% yield, respectively. For
comparison, the latter result is identical to what has
previously been published in the synthesis of 9 from methyl
†
experiments using a pre-heated oil bath (entry 11, Table 1).
A similar tendency was found when starting from
†
-bromopyridine (entry 2 and 3, Table 1). To this end, it
3
should be noticed that microwave heating is now generally
considered as having only thermal effects although some
discussion is still active in the literature regarding a specific
2-iodobenzoate applying Cu(I) as cocatalyst and stirring
two days at room temperature.
‘
microwave effect’.
3
3
We generally used palladium acetate as pre-catalyst but
observed in most cases a significantly improved yield when
introducing a phosphine ligand. This could be explained by
a stabilizing effect of the phosphine ligand on the reactive
palladium species, or by a facilitated reduction of the
palladium (II) to a palladium(0) species as previously
discussed for example the palladium-catalyzed Heck
In contrast to the successful reactions using 2- and
3
4
7
-substituted benzoic acid methyl esters, the corresponding
-bromosubstituted substrate gave compound 7 in a poor
% yield from a complex mixture of reaction products. In
the reaction of 2-bromo-3-hydroxypyridine, the 3-hydroxy
group participates in an intramolecular cyclization and the
expected disubstituted acetylenic product was, therefore,
not isolated. Instead, the further cyclized 2-phenyl-
furo(3,2b)pyrrole 5 was obtained in 33% yield. This result
corresponds to what has been reported by Sakamoto et al.
for the reaction of 2-iodo-3-hydroxypyridine with phenyl-
3
1,32
coupling.
Using either palladium acetate/tri(o-tolyl)-
phosphine (entry 16, Table 1) or tetrakis(triphenyl-
phosphine)palladium (entry 15, Table 1) very high yields
of 2 were obtained. Regarding the base, sodium acetate
turned out to be superior to aqueous potassium carbonate
and, in particular, triethylamine, for which only poor yield
was obtained (entry 7, Table 1).
34
acetylene.
In order to study the scope of this reaction, a number of aryl
halides and heteroaryl halides were subjected to this
transformation (Table 2). The yields are highly substrate-
Table 2. Coupling reactions of 1-phenyl-2-trimethylsilyl)acetylene (1)
a
a
Ar–X
Product, yield (%)
Ar–X
Product, yield (%)
b
2
2
71 (61)
7 (7)
b
90 (74)
8 84 (60)
c
3
4
5
(39)
9 85 (60)
9 85 (70)
10 44 (37)
d
50 (40)
e
(33)
6
55 (57)
11 84 (60)
a
3
Numbers in parentheses are isolated yields obtained without the use of (o-tol) P.
Average of two determinations.
b
c
d
e
3
2
5% isolated yield obtained with TZ140 8C.
.5 min, 600 W, 120 8C.
From 2-bromo-3-hydroxypyridine further cyclized 5 was obtained.

2700
U. S. Sørensen, E. Pombo-Villar / Tetrahedron 61 (2005) 2697–2703
Furthermore, it should be mentioned that neither phenyl
bromide nor phenyl iodide gave the desired product,
although trace amounts of diphenylacetylene had apparently
been formed in the latter case (TLC). Generally, good
results were obtained from heterocyclic aryl halides. The
two pyrimidine derivatives 10 and 11 were prepared from
their respective bromides. An early study of Sonogashira
couplings on iodopyrimidines previously reported the
synthesis of 10 in high yield (93%) from 2-iodopyrimidine
and phenylacetylene. In contrast, we isolated 10 in 44%
yield when starting from the corresponding 2-bromo-
pyrimidine, whereas the more reactive 5-bromopyrimidine
gave the novel compound 11 in up to 83% isolated yield. As
observed for the pyrimidines, pyridines having the halide
positioned meta to the heterocyclic nitrogen atom gave the
best results in this reaction (Table 2). It should be noted, that
silicon in analogy with the mechanism recently argued by
Itami et al. to explain the palladium-catalyzed coupling of
alkenyl silanes with aryl- and vinyl halides in the presence
3
7
of TBAF.
Fluoride-induced silicon to Pd transmetallation has been
invoked in Pd-catalyzed cross-coupling reactions by
Hiyama et al. To study this, we carried out a number of
3
5
38
experiments in which the coupling of the trimethylsilyl-
acetylene and the aryl halide was carried out in the presence
of only TBAF and palladium acetate. Interestingly, 2 could
in fact be isolated in good yield from 3-iodopyridine using
this procedure (Scheme 2).
3
has been reported synthesized from the corresponding
heterocyclic triflate using conventional Sonogashira
coupling conditions in 68% yield in the presence of
copper.
1
6
To further broaden the versatility of the reaction we were
also interested in introducing functionalized substituents via
the alkyne substrate.
Scheme 2.
Despite this result, the same method used on 2- and
5-bromopyrimidine gave low yields of products (8 and 4%,
respectively) together with many side-products, and when
Moreover, using as substrate 4-(trimethylsilylethynyl)-
benzaldehyde (12) or 2-(trimethylsilylethynyl)aniline (13)
it was possible to introduce an aldehyde moiety as well as an
amino group and obtain the desired coupling products 15
and 16 in 60 and 81% yield, respectively (Scheme 1). Thus,
neither of these, respectively, electron-withdrawing and
electron-donating functional groups appear to significantly
affect the reactivity of the phenylacetylene substrate,
applied to aldehyde 12, reaction with 3-iodopyridine gave
1
5 in 23% isolated yield. Following the addition of TBAF
the reaction was in all cases exothermic, and the reaction
mixture instantly turned black. In a control experiment,
applying an identical procedure, 3-iodopyridine was treated
with phenylacetylene (Scheme 2) in the presence of TBAF.
This experiment proceeded without the initial development
of heat and the reaction mixture did only slowly turn black.
Interestingly, the desired product 2 was isolated in similarly
high yield (81%) as in the reaction with trimethylsilyl-
acetylene 1. Thus, on the basis of this control experiment it
cannot be concluded whether a transmetallation pathway is
operating or if TBAF simply causes desilylation to give
phenylacetylene being the actual substrate in the cross-
coupling reaction.
suggesting tolerance to a wide range of substituents. Finally,
0
3
,3 -ethynediyl-bis-pyridine (17) was synthesized in high
yield from 14 whereas an attempt to introduce an aliphatic
substituent, using 1-(trimethylsilyl)-1-pentyne, was
unsuccessful.
In summary, a procedure for diarylacetylene synthesis via
the direct coupling of activated aryl- and heteroaryl
bromides and iodides with 1-aryl-2-trimethylsilylacetylenes
has been developed. It avoids the use of a copper(I) iodide
cocatalyst and is carried out by means of microwave heating
with short reaction times at elevated temperature.
3. Experimental
3
.1. General methods
Reagents and solvents were purchased from commercial
sources and used without further purification unless
otherwise stated. Melting points were determined in open
capillaries and are uncorrected. Microwave irradiation was
performed using a MLS-Ethos 1600 instrument or in one
case (Table 1, entry 14) by use of a SmithCreatore
instrument. Column chromatography (CC) was performed
Scheme 1.
We have not investigated the reaction mechanism of this
3
6
transformation and, as discussed elsewhere, it is not clear
whether it takes place via for example, a carbopalladation
pathway or via transmetallation between palladium and

U. S. Sørensen, E. Pombo-Villar / Tetrahedron 61 (2005) 2697–2703
2701
using silica gel 60 (0.040–0.063 mm) or prepacked silica gel
colums (50 or 70 g). Compounds were visualized on TLC
using UV light and KMnO spraying reagent. Proton and
(2.5 min oven setting 600 W, internal temperature 120 8C,
2-bromo-6-methylpyridine (2.9 mmol, 0.50 g), 1-phenyl-2-
trimethylsilylacetylene (8.9 mmol, 1.50 g), palladium
4
carbon NMR spectra were recorded on a 400 MHz
instrument at 400 and 100 MHz, respectively. Mass
spectrometry analyses were obtained using an LC/MSD
instrument.
acetate (0.14 mmol, 32.0 mg), Bu NCl (2.9 mmol,
4
810 mg), and sodium acetate (11.6 mmol, 951 mg) in dry
DMF (50 ml)). Isolated as the 1,5-naphthalenedisulfonate
salt (crystallized from MeOH—EtOH-Et O), 380 mg
2
(
47%); mp 296–297 8C. Spectra from corresponding free
1 42 1
3.1.1. General procedure for the synthesis of 2-(phenyl-
ethynyl)arenes. Synthesis of 3-(phenylethynyl)pyridine
base: H NMR in correspondence with literature; H NMR
(CDCl ) d 2.57 (s, 3H), 7.05–7.10 (m, 1H), 7.31–7.36 (m,
4H), 7.51–7.62 (m, 3H); C NMR (CDCl
89.0, 122.4, 122.6, 124.4, 128.3, 128.5, 128.8, 132.0, 136.4,
3
1
3
(
(
(
2). Method A (microwave heating). 3-Iodopyridine
2.50 mmol, 512 mg), 1-phenyl-2-trimethylsilylacetylene
5.00 mmol, 872 mg), palladium acetate (0.125 mmol,
) d 24.7, 88.9,
3
C
C
142.7, 158.9. MS (ES ) m/z 194 ([MC1] , 100). Anal.
Calcd for C38 $0.5 H O: C, 66.75; H, 4.57; N,
2
8.1 mg), Bu NCl (2.50 mmol, 695 mg), and sodium
4
H
30
N
2
O
6
S
2
2
acetate (10.0 mmol, 820 mg) in dry DMF (50 ml) were
heated under argon in the Ethos 1600 microwave oven for
4.10; O, 15.20; S, 9.38. Found: C, 66.55; H, 4.53; N, 4.08;
O, 15.23; S, 9.32.
1
4
1
5 minutes regulating the power (initially 450 W thereafter
0–50 W) in order to keep the temperature constant at
00 8C. After cooling to room temperature, the reaction
3.1.6. 2-phenyl-furo[3,2-b]pyridine (5). Method A
(2-bromo-3-hydroxypyridine (5.75 mmol, 1.00 g), 1-phenyl-
2-trimethylsilylacetylene (11.5 mmol, 1.98 g), palladium
mixture was added saturated aqueous NaHCO3 and
extracted three times with EtOAc. The combined organic
phases were dried (MgSO ), filtered, and evaporated to
acetate (0.28 mmol, 64.0 mg), Bu NCl (5.75 mmol, 1.6 g),
4
and sodium acetate (23.0 mmol, 1.9 g) in dry DMF (50 ml).
Reaction temperature 140 8C, 15 min). Solid, 376 mg
4
dryness and the residue purified by CC (0–10% EtOAc in
hexane) to give 2 as a solid in 75% yield (335 mg); mp 47.8–
3
4
1
(33%), mp 91–93 8C (lit. mp 88–89 8C). H NMR in
34,43 1
3
9
9.0 8C (lit. mp 50–51 8C). H NMR in correspondence
1
4
with literature;
correspondence with literature;
7.49 (m, 5H), 7.72–7.92 (m, 3H), 8.50–8.53 (m, 1H);
NMR (CDCl ) d 102.2, 118.0, 118.9, 125.4, 129.0, 129.7,
H NMR (CDCl ) 7.05–
3
3
9 1
13
H NMR (CDCl ) d 7.20–7.25 (m, 1H),
3
C
7
8
8
1
.30–7.36 (m, 3H), 7.51–7.56 (m, 2H), 7.73–7.79 (m, 1H),
3
1
.50–8.55 (m, 1H), 8.75–8.79 (m, 1H); C NMR (CDCl ) d
3
C
C
129.8, 146.2, 148.1, 149.2, 159.8. MS (EI ) m/z 195 (M ,
100). Anal. Calcd for C H NO: C, 79.98; H, 4.65; N, 7.17;
O, 8.20. Found: C, 79.93; H, 4.82; N, 7.16; O, 8.10.
3
6.0, 92.7, 120.4, 122.5, 123.0, 128.4, 128.8, 131.7, 138.4,
48.5, 152.2. MS (ES ) m/z 180 ([MC1] , 100). HRMS:
1
3 9
C
C
Calcd for C H N 180.0813, found 180.0816.
13 10
3.1.7. 3-(Phenylethynyl)quinoline (6). Method A (using in
addition 10 mol % tri(o-tolyl)phosphine). Solid, 316 mg
3
.1.2. Method B (conventional heating). These experi-
1
(55%), mp 67–70 8C. H NMR (CDCl ) d 7.20–7.71 (m,
ments (Table 1) were carried out exactly identical to the
above described (method A), except that the reaction
mixture was put in a preheated (100 8C) oil bath for
3
1
8H), 8.05–8.10 (m, 1H), 8.20 (s, 1H), 8.95 (s, 1H). C NMR
3
(CDCl ) d 86.6, 92.6, 117.4, 122.6, 127.1, 127.2, 127.5,
3
15 min, cooled to room temperature, and worked up as
described for method A.
128.4, 128.8, 129.3, 130.0, 131.7, 138.2, 146.7, 152.0. MS
(ES ) m/z 230 ([MC1] , 100). HRMS: Calcd for C H N
C
C
1
7 12
230.0970, found 230.0970.
3.1.3. Method C (Synthesis of 2 using tetrabutylammo-
nium fluoride (TBAF) in THF). 3-Iodopyridine
3.1.8. Methyl 4-(phenylethynyl)benzoate (7). Method A.
Oil, 40 mg (7%). H NMR in correspondence with
1
(
(
2.87 mmol, 588 mg), 1-phenyl-2-trimethylsilylacetylene
4.30 mmol, 750 mg), and palladium acetate (0.14 mmol,
4
4 1
literature;
(m, 7H), 7.98–8.02 (m, 2H). MS (EI ) m/z 236 (M , 100).
H NMR (CDCl ) d 3.92 (s, 3H), 7.20–7.60
3
C
C
32.2 mg) in dry THF (3 ml) was dropwise added in a 1 M
solution of TBAF in THF (4.30 mmol) and stirred under
argon 3 h at 65 8C. After cooling to rt, the reaction mixture
was added saturated aqueous NaHCO and extracted three
3.1.9. Methyl 3-(phenylethynyl)benzoate (8). Method A
(using in addition 10 mol % tri(o-tolyl)phosphine). Solid,
3
4
5
1
times with EtOAc. The combined organic phases were dried
(
498 mg (84%), mp 77.0–78.2 8C (lit. mp 77–79 8C). H
46 1
MgSO ), filtered, and evaporated to dryness. Compound 2
4
NMR in correspondence with literature; H NMR (CDCl3)
3.93 (s, 3H), 7.34–7.46 (m, 4H), 7.52–7.57 (m, 2H), 7.68–
was isolated as a dark solid in 82% yield (423 mg) by flash
chromatography (0–10% EtOAc in hexane). Compound
characterization ( H NMR and MS) showed that the isolated
1
3
7.72 (m, 1H), 7.97–8.02 (m, 1H), 8.19–8.23 (m, 1H).
NMR (CDCl ) d 52.3, 88.3, 90.3, 122.9, 123.8, 128.4, 128.5,
C
1
3
C
128.6, 129.2, 130.5, 131.7, 132.8, 135.7, 166.5. MS (EI )
product was identical to 2 as described above for method A.
C
m/z 236 (M , 100).
3
.1.4. 2-(Phenylethynyl)pyridine (3). Method A. Oil,
73 mg (39%). H and C NMR in correspondence with
1
13
1
literature;
3.1.10. Methyl 2-(phenylethynyl)benzoate (9). Method A
(from methyl 2-iodobenzoate, using in addition 10 mol %
4
0,41 1
H NMR (CDCl ) d 7.18–7.22 (m, 1H), 7.32–
3
1
tri(o-tolyl)phosphine). Oil, 505 mg (85%). H NMR in
7
8
1
.36 (m, 3H), 7.48–7.52 (m, 1H), 7.57–7.65 (m, 3H), 8.58–
.62 (m, 1H); C NMR (CDCl ) d 88.6, 89.2, 122.2, 122.7,
1
3
47,48 1
3
correspondence with literature;
(s, 3H), 7.31–7.65 (m, 8H), 7.92–7.98 (m, 1H). C NMR
H NMR (CDCl ) 3.95
3
C
27.1, 128.4, 129.0, 132.0, 136.2, 143.4, 150.0. MS (ES )
13
C
m/z 180 ([MC1] , 100).
(CDCl ) d 52.2, 88.2, 94.3, 123.3, 123.7, 127.9, 128.4,
3
C
28.5, 130.5, 131.3, 131.7, 131.9, 134.0, 166.7. MS (ES )
1
m/z 259 ([MCNa] , 100).
C
3
.1.5. 2-Methyl-6-(phenylethynyl)pyridine (4). Method A

2702
U. S. Sørensen, E. Pombo-Villar / Tetrahedron 61 (2005) 2697–2703
3
(
1
.1.11. 2-(Phenylethynyl)pyrimidine (10). Method A
using in addition 10 mol % tri(o-tolyl)phosphine). Solid,
References and notes
3
5
1
97 mg (44%), mp 84–86 8C (lit. mp 84–85 8C). H NMR
1. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467–4470.
(
(
CDCl ) d 7.15–7.22 (m, 1H), 7.32–7.40 (m, 3H), 7.62–7.69
3
1
m, 2H), 8.71–8.76 (m, 2H). C NMR (CDCl ) d 77.5, 87.9,
3
3
2. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627–630.
C
19.7, 121.2, 128.7, 129.7, 132.5, 153.2, 157.3. MS (ES )
1
C
m/z 181 ([MC1] , 100). HRMS: Calcd for C H N
2 9 2
1
3. Negishi, E.-i.; Anastasia, L. Chem. Rev. 2003, 103,
1979–2017.
1
81.0766, found 181.0766.
4
5
6
7
8
9
. Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93,
59–263. Cassar, L. J. Organomet. Chem. 1975, 93, 253–257.
2
3
.1.12. 5-(Phenylethynyl)pyrimidine (11). Method A
using in addition 10 mol % tri(o-tolyl)phosphine).
. Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y.
J. Org. Chem. 1981, 46, 2280–2286.
. Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995,
(
Solid, 375 mg (83%), mp 51.5–53.5 8C. H NMR
1
(
(
CDCl ) d 7.35–7.42 (m, 3H), 7.53–7.58 (m, 2H), 8.85
3
2
7, 127–160.
. Nguefack, J.-F.; Bolitt, V.; Sinou, D. Tetrahedron Lett. 1996,
7, 5527–5530.
. B o¨ hm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000,
679–3681.
1
s, 2H), 9.14 (s, 1H). C NMR (CDCl ) d 82.3, 96.3,
3
3
1
19.9, 121.8, 128.6, 129.4, 131.8, 156.7, 158.6. MS
C
3
C
(
EI ) m/z 180 (M , 100). Anal. Calcd for C H N : C,
12 8 2
7
1
9.98; H, 4.47; N, 15.54. Found: C, 79.83; H, 4.55; N,
5.30.
3
. Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I.
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1
1
1
0. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem.
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3
.1.13. 4-(3-Pyridylethynyl)benzaldehyde (15). Method A
(
using in addition 10 mol % tri(o-tolyl)phosphine). Solid,
09 mg (60%); a sample was recrystallized (EtOAc/hexane)
1. Dyatkin, A. B.; Rivero, R. A. Tetrahedron Lett. 1998, 39,
3647–3650.
2. Huang, S.; Tour, J. M. J. Am. Chem. Soc. 1999, 121,
3
for mp and elemental analysis; mp 98.5–99.3 8C. H NMR
1
(
CDCl ) d 7.29–7.35 (m, 1H), 7.68–7.73 (m, 2H), 7.82–7.93
3
4
908–4909.
(
1
m, 3H), 8.57–8.63 (m, 1H), 8.78–8.83 (m, 1H), 10.03 (s,
1
H). C NMR (CDCl ) d 89.7, 91.6, 119.7, 123.1, 128.7,
3
13. Preliminary results on this work have previously been
published in two posters: (a) Sørensen, U. S.; Wede, J.;
Pombo-Villar, E. 5th Electronic Conf. Synth. Org. Chem. 2001
http://www.mdpi.net/ecsoc-5/e0019/e0019.htm. (b) Sørensen,
U. S.; Wede, J.; Pombo-Villar, E. 12th Eur. Symposium Org.
Chem. 2001, abstract P2-124.
3
C
29.6, 132.2, 135.8, 138.6, 149.2, 152.4, 191.3. MS (ES )
1
m/z 208 ([MC1] , 100). Anal. Calcd for C H NO:
C
1
4 9
C, 81.14; H, 4.38; N, 6.76. Found: C, 80.81; H, 4.52; N,
6
.89.
1
4. Koseki, Y.; Omino, K.; Anzai, S.; Nagasaka, T. Tetrahedron
Lett. 2000, 41, 2377–2380.
3
.1.14. 2-(3-Pyridylethynyl)aniline (16). Method A (using
in addition 10 mol % tri(o-tolyl)phosphine). Solid, 394 mg
81%); a sample was recrystallized (EtOAc) for mp and
elemental analysis; mp 113.5–115.0 8C (lit. mp 104–
15. Halbes, U.; Pale, P. Tetrahedron Lett. 2002, 43, 2039–2042.
16. Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.-i.;
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2773–2779.
(
4
9
1
13
1
06 8C). H NMR and C NMR in correspondence with
literature; H NMR (CDCl ) d 4.32 (br s, 2H), 6.70–6.77
4
9 1
3
(
(
1
1
m, 2H), 7.13–7.20 (m, 1H), 7.24–7.31 (m, 1H), 7.35–7.41
m, 1H), 7.76–7.82 (m, 1H), 8.50–8.55 (m, 1H), 8.74 (s,
18. Gedye, R. N.; Rank, W.; Westaway, K. C. Can. J. Chem. 1991,
6
9, 706–711.
9. Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett.
001, 3, 4107–4110.
0. Abramovitch, R. A. Org. Prep. Proced. Int. 1991, 23,
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–47.
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1
3
H). C NMR (CDCl ) d 89.4, 91.2, 107.0, 114.5, 118.0,
1
2
2
2
3
2
20.5, 123.1, 130.3, 132.3, 138.2, 148.0, 148.5, 152.0. MS
C
C
(ES ) m/z 195 ([MC1] , 100). Anal. Calcd for
C H N $0.05 EtOAc: C, 79.81; H, 5.28; N, 14.10.
6
1
3 10 2
Found: C, 79.86; H, 5.32; N, 14.45.
1
0
3
(
3
.1.15. 3,3 -Ethynediyl-bis-pyridine (17). Method A
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1
2
3. Caddick, S. Tetrahedron 1995, 51, 10403–10432.
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5
69 mg (82%); mp 53–56 8C (lit. mp 60–62 8C). H NMR
0
1
2
(
CDCl ) d 7.26–7.32 (m, 2H), 7.80–7.86 (m, 2H), 8.55–8.60
3
´
´
25. Langa, F.; Cruz, P. D. L.; Hoz, A. D. L.; Dıaz-Ortiz, A.; Dıez-
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1
3
(
m, 2H), 8.78 (s, 2H). C NMR (CDCl ) d 89.2, 119.8,
3
C C
23.1, 138.5, 149.1, 152.3. MS (ES ) m/z 181 ([MC1] ,
00).
1
1
2
7. Kuhnert, N. Angew. Chem. Int. Ed. Engl. 2002, 41,
863–1866.
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2
Acknowledgements
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The authors thank Hans Peter Weber for his contribution to
the experimental work, and Professor Scott Denmark for a
copy of his manuscript in advance of publication.

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4