The first Cu- and amine-free Sonogashira-type cross-coupling in the C-6-alkynylation of protected 2′-deoxyadenosine

Article abstract of DOI:10.1016/j.tet.2009.03.064

The Sonogashira cross-coupling reaction offers a convenient route to C(sp)-C(sp²) bond formation. Although the Sonogashira reaction has traditionally been carried out in the presence of Pd catalyst and a co-catalyst of Cu(I) salt, the use of Cu(I) salt is often not efficient because it leads to the formation of unwanted side-products. This has prompted interest in recent years in the development of Cu-free Sonogashira cross-coupling reaction conditions. In addition, the development of Cu-free Sonogashira cross-coupling conditions for the alkynylation of nucleoside derivatives remains largely unexplored. Herein, we demonstrate that Cu- and amine-free Sonogashira-type cross-coupling lead to successful alkynylation of aryl bromides and heteroaryl bromides. For the first time, we have extended this method for the alkynylation of protected 2′-deoxyadenosine at the C-6 position.

Full text of DOI:10.1016/j.tet.2009.03.064

Tetrahedron 65 (2009) 4085–4091
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The first Cu- and amine-free Sonogashira-type cross-coupling
in the C-6-alkynylation of protected 20-deoxyadenosine
*
Felix N. Ngassa , Erick A. Lindsey, Brandon E. Haines
Department of Chemistry, Grand Valley State University, 1 Campus Drive, Allendale, MI 49401, USA
a r t i c l e i n f o
a b s t r a c t
The Sonogashira cross-coupling reaction offers a convenient route to C(sp)–C(sp2) bond formation. Al-
though the Sonogashira reaction has traditionally been carried out in the presence of Pd catalyst and
a co-catalyst of Cu(I) salt, the use of Cu(I) salt is often not efficient because it leads to the formation of
unwanted side-products. This has prompted interest in recent years in the development of Cu-free So-
nogashira cross-coupling reaction conditions. In addition, the development of Cu-free Sonogashira cross-
coupling conditions for the alkynylation of nucleoside derivatives remains largely unexplored. Herein, we
demonstrate that Cu- and amine-free Sonogashira-type cross-coupling lead to successful alkynylation of
aryl bromides and heteroaryl bromides. For the first time, we have extended this method for the alky-
nylation of protected 20-deoxyadenosine at the C-6 position.
Article history:
Received 5 March 2009
Accepted 13 March 2009
Available online 28 March 2009
Keywords:
Alkynylation
Cross-coupling
Deoxyadenosine
Nucleosides
Sonogashira
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
additives.5b,12b,14 Modifications in the original Sonogashira cross-
coupling reaction have resulted in the reaction being easily ame-
Alkynes are commonly found in many natural products and
biologically active compounds.1 The versatility of alkynes as im-
portant synthetic intermediates has prompted interest in designing
efficient methods to incorporate alkynes in organic molecules. One
commonly used method for incorporation of alkynes in organic
molecules, through the formation of C–C bonds, is the Sonogashira
cross-coupling method.2 The Sonogashira coupling reaction has
been extensively studied since its discovery in 1975. The Sonoga-
shira cross-coupling reaction involves the coupling of a terminal
alkyne with an aryl or vinyl halide or triflate, using a palladium
catalyst and a Cu(I) salt as co-catalyst.3 The creation of the C(sp)–
C(sp2) bond makes the Sonogashira cross-coupling reaction one of
the most important reactions in synthetic organic chemistry. It has
been reported that the use of CuI does not always have a positive
outcome on effective Sonogashira cross-coupling reactions.4 This is
because the use of CuI results in unwanted side-reactions, such as
the oxidative homocoupling of alkynes to form the so-called Glaser
product.5 This side-reaction has driven the modification of the
original Sonogashira cross-coupling reaction.6–9 To date, examples
of Pd-free,6 Cu-free,10 amine-free,11 ligand-free,12 and solvent-
free5b conditions have been reported. The Sonogashira cross-
coupling reaction has also been performed in the presence of
water as solvent,12b,13 or using tetrabutyl ammonium salts as
nable on a laboratory and industrial scale.
Modified nucleosides play important roles in many biological
processes. Nucleoside analogs, substituted at the C-6 position, have
been shown to display a broad range of biological activities.15–18
The Sonogashira cross-coupling reaction provides easy access to 6-
alkynylpurine nucleosides, which would otherwise be difficult to
synthesize using other conventional coupling reactions. Successful
Sonogashira cross-coupling reaction has been reported using 6-
chloropurine and 6-iodopurine nucleosides with 1-hexyne, and
employing Pd(PPh3)4/CuI/TEA as the catalytic system.19 However,
only one terminal alkyne was used and there is no evidence that the
catalytic system could be extended, with equal success, to other
terminal alkynes.
Nucleosides can be covalently modified to form fluorescent an-
alogs.20 Fluorescent nucleoside analogs can serve as valuable probes
in cellular and signal transduction pathways.21 The synthesis of
modified nucleosides by Pd-catalysis has been reported.3c,22 The
alkynylation of nucleosides by Sonogashira cross-coupling has also
been reported.3c,20,23 However, most of the successful alkynylation
reactions reported so far have involved 8-bromoadenosine and
8-bromoguanosine with terminal acetylenes. Interestingly, de-
velopment of a catalytic system for the alkynylationat the 6-position
of 6-bromo-20-deoxyadenosine has not been fully explored. To the
best of our knowledge, very limited information exists in the liter-
ature on the Sonogashira cross-coupling of 6-bromo-20-deoxy-
adenosine with terminal alkynes to generate 6-alkynylated-20-
deoxyadenosine derivatives.
* Corresponding author. Tel.: þ1 616 331 3803.
E-mail address: ngassaf@gvsu.edu (F.N. Ngassa).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.064

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F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
Most biological activities studies with modified nucleosides
In the course of the optimization experiments, some important
lessons were learned. The combination of Pd2(dba)3/CuI, the li-
gands L-1, L-2, L-3, or L-4, any of the solvents, and either Et3N or
DABCO, at 90 ꢀC, 50 ꢀC, or ambient temperature led to no significant
product formation over a 24 h period. However, the use of
Pd(PPh3)4/CuI, the ligands L-1 or L-2, Et3N or DABCO, and the sol-
vent DMF or toluene led to significant improvement in the yield at
90 ꢀC and 50 ꢀC. Although the use of PdCl2(CH3CN)2 gave better
results when compared to Pd2(dba)3, the yields were still lower
when compared to Pd(PPh3)4. Our initial experiments established
the combination Pd(PPh3)4/CuI/L-1/Et3N in DMF at 90 ꢀC as the
optimal conditions for the common Sonogashira coupling.
Although results from our optimization studies using Et3N, DMF,
Pd(PPh3)4, and L-1 at 90 ꢀC were largely satisfactory, we were still
concerned with the occasional appearance of the Glaser product, as
judged by GC–MS analysis. To combat the problem of Glaser cou-
pling, Cu-free Sonogashira cross-coupling reactions were explored.
Three Pd species, Pd2(dba)3, Pd(PPh3)4, and PdCl2(CH3CN)2, were
used in these Cu-free cross-coupling reactions, with acetonitrile,
DMF, and toluene as solvents (Table 1). The Pd2(dba)3/L-1 catalytic
system provided no coupling under the Cu-free conditions, while
the PdCl2(CH3CN)2/L-1 gave a modest 72% yield. However, the
Pd(PPh3)4/L-1 catalytic system was extremely efficient under these
conditions producing a 91% yield of the Sonogashira cross-coupling
product. The optimum conditions for the Sonogashira cross-cou-
pling reactions were found to require the use of L-1 and Pd(PPh3)4
at 90 ꢀC in acetonitrile (Table 1, entry 2).
have been limited to the 6-arylpurine ribonucleosides, with a few
studies on the 6-alkynylpurine ribonucleosides. However, bi-
ological studies on the 6-alkynylpurine deoxyribonucleosides re-
main largely unexplored. One reason why the potential biological
activities of 6-alkynylpurine deoxyribonucleosides have not been
fully explored could be the difficulty in synthesizing 6-alky-
nylpurine deoxyribonucleosides through cross-coupling reactions
between the labile deoxyribonucleosides and terminal alkynes.
Although the common Sonogashira cross-coupling method works
well in the cross-coupling of terminal alkynes with aryl halides and
heteroaryl halides, this method may not necessarily be extended to
deoxyribonucleosides with equal success. Although many different
variations of the common Sonogashira cross-coupling methods
have been reported in the literature, the application of these
methods with protected 20-deoxyribonucleosides requires a careful
and systematic approach; the cross-coupling method must be
compatible with the protecting group on the sugar moiety and be
tolerant to the lability of the nucleosidic bonds. As a result of our
ongoing interest in transition metal-mediated syntheses of modi-
fied nucleosides,24 we decided to evaluate the common Sonoga-
shira cross-coupling method and the modified versions in the
coupling of protected 20-deoxyadenosine with terminal alkynes.
Herein, we report a convenient Sonogashira cross-coupling pro-
tocol for the alkynylation of aryl bromides, heteroaryl bromides,
and 6-bromo-20-deoxyadenosine.
In order to study the scope of our optimized reaction conditions,
a number of aryl bromides and heteroaryl bromides containing
a wide array of functional groups were subjected to Sonogashira
cross-coupling with phenylacetylene (Table 2). The yields were
good for all substrates; simple aromatic, heteroaromatic, and ex-
tended aromatic substrates. Irrespective of the substituents on the
aromatic substrates, products were obtained for activated and less
activated aryl halides. No significant difference was observed in the
reactivity between 2-bromosubstituted and 4-bromosubstituted
substrates when the electron-donating group was a methyl group
(Table 2, entries 4 and 7). However, there was a significant differ-
ence in the reactivity between 2-bromosubstituted and 4-bromo-
substituted substrates when the electron-donating group was
a methoxy group (Table 2, entries 6 and 8). The reaction with ortho-
bromoanisole proceeded to afford the desired cross-coupling
product in 94% yield (Table 2, entry 6), while the reaction with para-
bromoanisole gave a modest 69% yield (Table 2, entry 8). In addi-
tion, aryl bromides showed selective reactivity in the presence of
fluorine and chlorine (Table 2, entries 3 and 5). In the reaction of 4-
bromo-2-chlorophenol, selective alkynylation was observed at the
4-bromo position given 53% of the desired product (Table 2, entry
3); there was no evidence of alkynylation at the 2-chloro position.
2. Results and discussion
We envisaged the establishment of a general synthetic route to
6-alkynylpurine deoxyribonucleoside derivatives through a Sono-
gashira-type cross-coupling reaction of protected 6-bromo-20-
deoxyadenosine with a series of terminal alkynes. The Sonogashira
cross-coupling reaction was carried out using 3 mol % Pd species
and 2 mol % CuI as the catalytic system. For initial optimization, we
chose bromobenzene and phenylacetylene as substrates, Pd2(dba)3,
PdCl2(CH3CN)2, and Pd(PPh3)4 as Pd species, L-1, L-2, L-3, and L-4 as
ligands, and Et3N and DABCO as bases (Fig. 1). The ligands were
chosen because of our previous experience with these ligands,24
and because Buchwald et al. had shown that biaryl dialkyl phos-
phine ligands are efficient at catalyzing the Sonogashira cross-
coupling reaction.4 Interestingly, in our hands, the Pd species and
ligand that were successful in the coupling of aryl chlorides with
terminal alkynes, as reported by Buchwald et al. did not work quite
as well in the coupling of aryl bromides with terminal alkynes. We
chose the more readily available Pd species, which were more
promising. In the optimization experiments, four different solvents
were tried at 50 ꢀC, 90 ꢀC, or ambient temperature (see Supple-
mentary data for a comprehensive table of results).
Pd Species:
Pd2(dba)3
Pd(PPh3)4
PdCl2(CH3CN)2
PPh2
Bu-tert
N
Cy
P
PPh2
PPh2
Ligands:
O
P
Bu-tert
Cy
PPh2
L-1
L-2
L-3
L-4
N
N
Bases:
Et3N
Cs2CO3
Figure 1. Pd species, ligands, and bases investigated.

F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
4087
Table 1
Table 2
Optimization study for the Cu- and amine-free Sonogashira cross-coupling of
phenylacetylene with bromobenzene
Sonogashira cross-coupling of phenylacetylene with aryl bromides
R
Br
Pd-species (6 mol%)
Ligand (12 mol%)
Pd(PPh3)4/L
R
+
Br
+
Cs2CO3, CH3CN
Cs2CO3, 90°C
2a-o
Entryb
1
Ar-X
Product
Time (h)
2
Yielda (%)
91
Entry Ligand Pd species
Solvent
Time (h) Yielda (%)
1
2
3
4
5
L-1
L-1
L-1
L-1
L-1
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
MeCN
MeCN
DMF
24
2
Mostly starting material
Br
Br
91
43
61
72
2a
2
8
2
Toluene
PdCl2(CH3CN)2 MeCN
2
2b
2c
2d
2e
2f
6
5
91
53
78
93
94
75
69
73
0
a
The percentage yield is the calculated yield of recovered product from an av-
NO2
erage of two runs. The presence or absence of the homocoupling product (Glaser
product) was ascertained by GC–MS.
Br
OH
3
Cl
Br
For the 2-bromosubstituted substrates, the electronic effect of the
substituents seemed to be important for the reactivity (Table 2,
entries 2, 4, and 5). The presence of the electron-withdrawing nitro
and fluoro groups resulted in 91 and 93% yield of the desired
products, respectively (Table 2, entries 2 and 5). In contrast, the
presence of the electron-donating methyl group resulted in a 78%
yield of the desired product (Table 2, entry 4). But, it is nebulous to
draw a conclusion on the role that the electronic effect has on the
reactivity of 2-bromosubstituted substrates since the presence of
electron-donating methoxy group at the ortho position resulted in
excellent yield of 94% (Table 2, entry 6). Results indicate that
electronic effect of the ortho-substituents is not the only important
factor in predicting the outcome of cross-coupling among aromatic
substrates. The presence of a heteroatom at the ortho position could
also result in a chelating effect that might affect the reactivity of the
substrate.25
In the case of the 4-bromosubstituted substrates, electronic ef-
fect of the substrates did not seem to be important in the reactivity
(Table 2, entries 7, 8, and 9). In the presence of the electron-
donating methyl and methoxy groups, the desired products
were obtained in 75% and 69% yields, respectively (Table 2, entries 7
and 8). Similarly, in the presence of the electron-withdrawing
acetyl group, the desired product was obtained in 73% yield
(Table 2, entry 9).
In order to assess the effect of steric hindrance on the cross-
coupling reaction, we decided to use the hindered aryl bromide
2,4,6-tri-tert-butylbromobenzene. Results showed that cross-
coupling was inhibited by bulky substituents on the benzene ring
since no product was obtained using 2,4,6-tri-tert-butyl-
bromobenzene as the substrate after 24 h (Table 2, entry 10). In
order to explore the versatility of our optimized cross-coupling
conditions, we decided to further test the viability using hetero-
cyclic aryl bromides. Using heterocyclic aryl bromides from the
pyridine and pyrimidine family, good yields of the desired prod-
ucts were obtained (Table 2, entries 11–13). The reactivity of 2-
bromopyridine was better than that of any of the pyrimidine
bromides. Using 2-bromopyridine as the substrate, the desired
cross-coupling product was obtained in 82% in just 1 h (Table 2,
entry 11). For the bromopyrimidine derivatives, 2-bromopyr-
imidine was more reactive than 5-bromopyrimidine (Table 2, en-
tries 12 and 13). This result is contrary to what had been reported,
where 5-bromopyrimidine was said to be more reactive than 2-
bromopyrimidine in a Cu-free Sonogashira-type coupling.26 Sat-
isfied with the results obtained for the heterocyclic aryl halides, we
decided to probe the generality of the cross-coupling reaction
using extended aromatic systems such as the naphthalene family
(Table 2, entries 14 and 15). Although the reactions in this series
were generally slower, the cross-coupled products were still
obtained in good to excellent yields. Comparing the two
4
3
CH3
Br
5
4
F
Br
OCH3
CH3
6
8
7
2g
2h
2i
2
Br
8
8
Br
OCH3
9
3
Br
COCH3
Br
10
11
12
13
14
2j
24
1
N
2k
2l
82
82
65
98
Br
Br
N
N
3
N
N
2m
2n
6
Br
Br
8
Br
15
2o
24
69
a
The percentage yield is the calculated yield of recovered product from an av-
erage two runs.
b
Reactions were carried out in acetonitrile at 90 ꢀC, with 1.0 equiv of aryl bro-
mides, 1.2 equiv of phenylacetylene, 0.06 equiv of Pd(PPh3)4, 0.12 equiv of 2-(di-tert-
butylphosphino)-1,10-biphenyl(L-1), and 2.4 equiv of Cs2CO3.
naphthalene systems, the least-hindered 2-bromonaphthalene
showed a faster reaction and gave an excellent yield of 98% com-
pared to 69% for 1-bromonaphthalene (Table 2, entries 14 and 15).
Next, we studied the coupling of 2-bromopyridine with various
acetylenes, using our optimal reaction conditions (Table 3). The
structure of the alkyne also had an effect on the efficiency of the
coupling reactions. Phenylacetylene reacted with 2-bromopyridine

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F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
Table 3
Table 4
Sonogashira cross-coupling of acetylenes with 2-bromopyridine
Sonogashira cross-coupling of acetylenes with 6-bromo-9[2-deoxy-3,5-bis-O-(tert-
butyldimethylsilyl)-
b
-
D
-erythro-pentofuranosyl]purine
Pd(PPh3)4/L
N
N
Cs2CO3
R
R
+
Br
R
CH3CN, 90°C
2k, 3a-e
Br
N
N
N
N
Entryb
1
Product
Time (h)
Yielda (%)
N
R
N
N
N
TBDMSO
TBDMSO
2k
1
82
Pd(PPh3)4/L
Cs2CO3
O
O
R
+
4a-i
CH3CN, 90°C
OTBDMS
OTBDMS
Yielda (%)
2
3
3a
3b
24
Mostly starting material
NO2
Entryb
1
Product
Time (h)
R
1
1
86
87
4a
6
69
OCH3
2
3
4b
4c
24
Mostly starting material
4
5
3c
NO2
3d
3e
5
3
54
78
6
60
OCH3
6
a
The percentage yield is the calculated yield of recovered product from an
average two runs.
4
5
6
4d
4e
4f
5
6
6
72
52
63
b
Reactions were carried out in acetonitrile at 90 ꢀC, with 1.2 equiv of acetylenes,
1.0 equiv of 2-bromopyridine, 0.06 equiv of Pd(PPh3)4, 0.12 equiv of 2-(di-tert-
butylphosphino)-1,10-biphenyl(L-1), and 2.4 equiv of Cs2CO3.
to give the cross-coupling product 3k in 82% yield (Table 3, entry 1).
With substituted phenylacetylenes, only the electron-rich
derivatives gave the cross-coupled product 3b in 86% yield (Table 3,
entry 3). The electron-poor phenylacetylene, 2-nitrophenyl-
acetylene, gave no cross-coupling product (Table 3, entry 2). The
extended aromatic substrate, 1-ethynylnaphthalene, gave the
cross-coupling product 3c in 87% yield (Table 3, entry 4). The simple
aliphatic alkynes reacted to give moderate to good yields of
the cross-coupling products 3d and 3e in 54% and 78% yields, re-
spectively (Table 3, entries 5 and 6).
CH3
7
8
4g
8
56
CH3
4h
4i
8
58
OCH3
CHO
9
24
Mostly starting material
Alkynylation at the C-6 position of ribonucleosides, using a cat-
alytic system with CuI, was previously reported with only a limited
application for the alkyne substrates.19 We conducted a series of
experiments to assess the efficiency of a Cu-free protocol in the
Sonogashira cross-coupling of the easily prepared halonucleoside
precursor 6-bromo-9[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-
a
The percentage yield is the calculated yield of recovered product from an
average two runs.
b
Reactions were carried out in acetonitrile at 90 ꢀC, with 1.2 equiv of acetylenes,
1.0 equiv of bromonucleoside, 0.06 equiv of Pd(PPh3)4, 0.12 equiv of 2-(di-tert-
butylphosphino)-1,10-biphenyl(L-1), and 2.4 equiv of Cs2CO3.
b
-D-erythro-pentofuranosyl]purine,27 with various terminal al-
kynes (Table 4). Generally good to modest yields were obtained for
some terminal alkynes (entries 1, 3, 4, and 6). However, the pres-
ence of electron-withdrawing nitro group or formyl group on the
phenylacetylene resulted in no cross-coupling product even after
24 h (entries 2 and 9). It is currently not clear why the electron-
withdrawing substituents are unreactive under this protocol. The
presence of electron-donating groups on the phenylacetylene
resulted in the desired coupling products, albeit, in comparably
lower yields than the unsubstituted phenylacetylene (entries 3, 6, 7,
and 8). Among phenylacetylene derivatives with electron-donating
substituents, those with ortho-substituents gave slightly better
yields than their para-substituted counterparts (entries 3, 6, 7, and
8). The reaction with 1-octyne, an aliphatic alkyne, gave 52% yield
of the desired coupling product (entry 5). For all the coupling re-
actions, the major NMR signals showed that the desired products
were obtained with no significant peaks resulting from a side-
product, except some minor uncharacterized impurities in some
cases. It should be noted that although the yields obtained for the
nucleoside couplings are moderate to good, it is the first time that
such modified Sonogashira cross-coupling conditions have been
applied to the C-6-alkynylation of 20-deoxyadenosine. It is also
important to note that cross-coupling reactions involving nucleo-
sides are generally difficult due to the many basic nitrogens on the
heterocyclic structure of nucleosides.
3. Conclusion
In summary, a Cu-free Sonogashira procedure for the cross-
coupling of functionally substituted aryl bromides, and heteroaryl
bromides with terminal alkynes has been developed. This pro-
cedure was successfully applied in the Sonogashira cross-coupling
of 6-bromo-20-deoxyadenosine with terminal alkynes of various
functionality. The reactions are tolerant to different functional
groups, generally result in reasonable to good yields, and proceed
under relatively mild conditions. Current work in our laboratories is
geared toward further optimization of the 6-bromo-20-deoxy-
adenosine reaction using different catalytic systems, and extending

F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
4089
the Sonogashira cross-coupling conditions to synthesis involving
4.4. General procedure (B) for the Pd-free Sonogashira cross-
coupling reactions
other halopurine nucleosides. We are currently studying the fluo-
rescent properties of the alkynylated deoxyadenosine derivatives,
in view of our interest in evaluating their potential biological ap-
plications. As a result of the challenge inherent in coupling re-
actions involving nucleosides, due to the large number of basic
nitrogens, which could potentially serve as ligands, the de-
velopment of catalytic systems, which can effectively result in
cross-coupling of terminal alkynes and modified nucleosides is
interesting. This work represents our initial contribution in this
endeavor, while work is continuing in our laboratory to optimize
the reaction even further with new catalytic systems.
CuI (0.0525 mmol), DABCO (0.121 mmol), Cs2CO3 (2 equiv, or
4 equiv), bromobenzene (0.5 mmol) as well as 3 mL DMF were
added to a screw cap vial. Phenylacetylene (0.6 mmol) was slowly
added, the mixture was placed under N2, and capped with a Teflon
coated cap. The mixture was placed in a 135 ꢀC oil bath and stirred
under N2 until completion. The resulting mixture was cooled to
room temperature, vacuum-filtered, and rinsed with hexane. The
residue was purified by flash column chromatography on silica gel,
eluting with hexane to give the desired product.
4. Experimental section
4.1. General methods
4.5. General procedure (C) for the Cu-free Sonogashira cross-
coupling reactions
The Pd species (0.030 mmol), ligand (0.060 mmol), Cs2CO3
(1.2 mmol), and solvent were added to a screw cap vial. The aryl
halide (0.5 mmol) was added and the mixture stirred at room
temperature for 25 min under N2. The desired alkyne (0.60 mmol)
was then added. The mixture was placed in a 90 ꢀC oil bath and
stirred under N2 until completion of reaction. The reaction mixture
was then cooled to room temperature, diluted with EtOAc, and
washed with water. The combined organic layers were dried over
anhydrous Na2SO4. After concentration, the residue was purified by
flash column chromatography on silica gel, eluting with the ap-
propriate hexane/EtOAc mixture to give the desired product.
Reactions were conducted in oven-dried vials under a nitrogen
atmosphere. All reactions were carried out in freshly distilled and
dried solvents. The ligands, Pd(PPh3)4, Pd2(dba)3, and all other re-
agents were obtained from commercial sources and were used
without further purification. The protons on the sugar unit are
numbered 10–50 beginning at the anomeric carbon and proceeding
via the carbon chain to the primary carbinol carbon. 1H NMR
spectra (300 MHz) and 13C spectra (75 MHz) were recorded on
a JEOL ECX300 spectrometer in CDCl3 and internally referenced to
residual CHCl3 (7.25 ppm, 1H). Chemical shifts are reported in parts
per million (ppm, d
). 1H NMR splitting patterns are designated as
singlet (s), doublet (d), triplet (t), quartet (q), or pentet (p). All first
order splitting patterns are assigned based on the appearance of the
multiplet. For those splitting patterns that could not be easily
visualized or interpreted, a designation of multiplet (m) was used.
Coupling constants are reported in hertz (Hz). TLC was carried out
on glass-backed Analtech TLC plates precoated with silica gel
4.6. Literature precedence
Our experimental procedure gave compounds with spectral
properties consistent with those in the literature for the following
compounds; 2a, 2b, 2d, 2f, 2g, 2h, 2i, 2k, 2l, 2m, and 2o (see
Supplementary data for details).
(250 mm layer thickness) containing a fluorescent indicator. Col-
umn chromatographic purifications were performed using 200–
300 mesh silica gel from Natland.
4.6.1. 2-Chloro-4-(phenylethynyl)phenol (2c)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
7.52–7.48 (m, 3HAr), 7.37–7.33 (m, 4HAr), 6.99 (d, 1HAr, J¼8.5 Hz),
5.68 (s, 1HOH); 13C NMR (75 MHz, CDCl3)
d
: 151.6, 132.2, 132.1, 131.6,
4.2. GC/MS conditions
128.5, 128.4, 123.2, 119.9, 116.7, 116.4, 88.9, 87.9; GC/MS
rt¼13.02 min, Mþ¼228.1 m/z; HRMS exact mass calculated for
C19H9ClO (MþþH) 229.0324, found 229.0321.
A Finnigan Focus GC/DSQ system with automated liquid sampler
and Supelco Equity 5 15 mꢁ0.25 mmꢁ0.25
mm was used with
a flow of ultra high purity He. The temperatures for the aryl ethers
in dichloromethane were inlet 220 ꢀC, oven 50 ꢀC for 2 min, ramp
to 270 ꢀC at 15 ꢀC/min. The flow was set to 50 mL/min, the split
ratio was 42:1, and the solvent delay was 1.05 min. The mass scan
range was 50–700 m/z. The syringe wash solvent was
dichloromethane.
4.6.2. 1-Fluoro-2-(phenylethynyl)benzene (2e)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
7.61–7.51 (m, 3HAr), 7.40–7.28 (m, 4HAr), 7.17–7.10 (m, 2HAr); 13C
NMR (75 MHz, CDCl3) : 140.3, 131.9, 131.6, 129.6, 128.5, 128.4,
d
128.3, 125.7, 123.7, 123.1, 93.5, 88.5, 20.9; GC/MS rt¼10.60 min,
Mþ¼197.1 m/z; HRMS exact mass calculated for C14H9F (MþþH)
197.0688, found 197.0690.
4.3. General procedure (A) for the common Sonogashira
cross-coupling reactions
4.6.3. 2-(Phenylethynyl)naphthalene (2n)
The Pd species (0.030 mmol), CuI (0.020 mmol), and the desired
solvent (1 mL) were added to a screw cap vial and capped with
a Teflon coated cap. The mixture was then stirred at room tem-
perature under N2 for 5 min. The ligand (0.060 mmol), amine
(1.2 mmol), and aryl halide (1.0 mmol) were added to the reaction
mixture. The alkyne (1.2 mmol) was slowly added and the reaction
mixture was placed in an oil bath maintained at a constant tem-
perature and stirred under N2. The resulting mixture was cooled to
room temperature, diluted with EtOAc, and washed with H2O. The
organic layer was dried over anhydrous Na2SO4, filtered, and then
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with hexane/
EtOAc to give the desired product.
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
8.09 (m, 1HAr), 7.86–7.82 (m, 3HAr), 7.63–7.60 (m, 3HAr), 7.54–7.50
(m, 2HAr), 7.42–7.36 (m, 3HAr); 13C NMR (75 MHz, CDCl3)
d: 131.8,
131.6, 128.5, 128.5, 128.2, 127.9, 126.8, 126.7, 90.0, 89.9; GC/MS
rt¼14.58 min, Mþ¼229.2 m/z; HRMS exact mass calculated for
C18H12 (MþþH) 229.0939, found 229.0940.
4.6.4. 2-((2-Methoxyphenyl)ethynyl)pyridine (3b)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
8.60 (d, 1HAr, J¼5 Hz), 7.65 (t, 1HAr, J¼7.7 Hz), 7.56–7.52 (m, 2HAr),
7.35–7.29 (m,1HAr), 7.22–718 (m,1HAr), 6.95–6.88 (m, 2HAr), 3.89 (s,
1HMe); 13C NMR (75 MHz, CDCl3)
d: 160.5, 150.0, 143.8, 136.1, 134.1,
130.6, 127.3, 122.6, 120.5, 111.6, 110.8, 92.7, 85.9, 55.9; GC/MS

4090
F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
rt¼12.95 min, Mþ¼209.1 m/z; HRMS exact mass calculated for
C14H11NO (MþþH) 210.0841, found 210.0845.
4.6.11. 6-(Oct-1-ynyl)-9-[20-deoxy-30,50-bis-O-(tert-butyl-
dimethylsilyl)-b-D-erythro-pentofuranosyl]purine (4e)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d
:
0
0
4.6.5. 2-(1-Naphthylethynyl)pyridine (3c)
8.86 (s, 1H2,8), 8.38 (s, 1H2,8), 6.50 (t, 1H1 , J¼6 Hz), 4.61 (m, 1H3 ),
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d
:
4.02 (q, 1H4 , J¼3 Hz), 3.86 (dd, 1H5 , J¼4, 11 Hz), 3.76 (dd, 1H5 , J¼3,
0
0
0
0
0
8.67 (s, 1HAr), 8.49 (d, 1HAr, J¼8.25 Hz), 7.88–7.83 (m, 3HAr), 7.70–
11 Hz), 2.62 (m, 1H2 ), 2.58 (t, 2HAl, J¼7 Hz), 2.44 (m, 1H2 ), 1.70 (m,
7.47 (m, 5HAr), 7.27–7.23 (m, 1HAr); 13C NMR (75 MHz, CDCl3)
d:
2HAl),1.46 (m, 2HAl),1.29 (m, 4HAl), 0.90 (d,18H, t-Bu), 0.10 (m, 3HAl,
150.3, 143.7, 136.3, 133.4, 133.2, 131.3, 129.6, 128.4, 127.1, 126.7,
126.3, 125.3, 122.9, 119.9, 99.9, 93.6, 87.6; GC/MS rt¼14.93 min,
Mþ¼229.1 m/z; HRMS exact mass calculated for C17H11N (MþþH)
230.0891, found 230.0894.
12H, –Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d: 152.5, 150.9, 143.6,
142.5, 134.9, 101.7, 88.2, 84.6, 76.2, 72.1, 62.9, 41.4, 31.4, 28.8, 28.2,
26.0, 25.8, 22.6, 20.1, 18.5, 18.1, 14.1, ꢂ4.48, ꢂ4.59, ꢂ5.29, ꢂ5.39.
HRMS exact mass calculated for C30H53N4O3Si2 (MþþH) 573.3578,
found 573.3661.
4.6.6. 2-(Hex-1-ynyl)pyridine (3d)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
4.6.12. 6-((2-Methylphenyl)ethynyl)-9-[20-deoxy-30,50-bis-O-(tert-
8.50 (m, 1HAr), 7.58 (m, 1HAr), 7.34 (m, 1HAr), 7.15 (m, 1HAr), 2.41 (t,
butyldimethylsilyl)-
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
8.96 (s, 1H2,8), 8.44 (s, 1H2,8), 7.68 (d, 1HAr, J¼7.6 Hz), 7.34–7.27 (m,
b-D-erythro-pentofuranosyl]purine (4f)
2H, J¼7 Hz), 1.64–1.40 (m, 4H), 0.91 (t, 3H, J¼7 Hz); 13C NMR
d:
(75 MHz, CDCl3) d: 149.8, 144.1, 136.1, 126.8, 122.3, 91.2, 80.4, 30.5,
22.1, 19.1, 13.7; GC/MS rt¼8.76 min, Mþ¼159.1 m/z; HRMS exact
2HAr), 7.21 (m, 1HAr), 6.52 (t, 1H1 , J¼6 Hz), 4.63 (m, 1H3 ), 4.04 (q,
0
0
mass calculated for C11H13N (MþþH) 160.1048, found 160.1052.
1H4 , J¼3 Hz), 3.86 (dd, 1H5 , J¼4, 11 Hz), 3.76 (dd, 1H5 , J¼3, 11 Hz),
0
0
0
0
0
2.69 (m, 1H2 ), 2.64 (s, 3HMe), 2.47 (m, 1H2 ), 0.90 (d, 18H, t-Bu), 0.09
4.6.7. 2-(Oct-1-ynyl)pyridine (3e)
(d, 12H, –Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d
: 152.6, 151.1, 143.9,
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
142.1, 141.7, 135.0, 133.1, 129.9, 129.7, 125.7, 121.4, 97.6, 88.2, 88.1,
84.6, 72.0, 62.8, 41.3, 26.0, 25.8, 21.0, 18.5, 18.1, ꢂ4.60, ꢂ4.70, ꢂ5.29,
ꢂ5.38. HRMS exact mass calculated for C31H47N4O3Si2 (MþþH)
579.3108, found 579.3177.
8.51 (d, 1HAr), 7.56 (td, 1HAr), 7.33 (d, 1HAr), 7.13 (m, 1HAr), 2.39 (t,
2HAl, J¼6.8 Hz), 1.59 (p, 2HAl, J¼6.8 Hz), 1.46–1.39 (m, 2HAl), 1.29–
1.24 (m, 4HAl), 0.85 (t, 3HAl); 13C NMR (75 MHz, CDCl3)
d: 149.8,
144.0, 136.1, 126.8, 122.3, 91.3, 80.4, 31.4, 28.7, 22.6, 19.4, 14.1; GC/
MS rt¼10.34 min, Mþ¼186.1 m/z; HRMS exact mass calculated for
C13H17N (MþþH) 188.1361, found 188.1363.
4.6.13. 6-((4-Methylphenyl)ethynyl)-9-[20-deoxy-30,50-bis-O-(tert-
butyldimethylsilyl)-
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
8.92 (s, 1H2,8), 8.44 (s, 1H2,8), 7.63 (d, 2HAr, J¼8 Hz), 7.19 (d, 2HAr
b-D-erythro-pentofuranosyl]purine (4g)
d
:
,
4.6.8. 6-(Phenylethynyl)-9-[20-deoxy-30,50-bis-O-(tert-butyl-
0
0
0
dimethylsilyl)-
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
8.93 (s, 1H2,8), 8.45 (s, 1H2,8), 7.75–7.71 (m, 2HAr), 7.42–7.35 (m,
b
-D-erythro-pentofuranosyl]purine (4a)
J¼8 Hz), 6.53 (d, 1H1 , J¼6 Hz), 4.63 (m, 1H3 ), 4.03 (q, 1H4 , J¼3 Hz),
0
0
0
d:
3.88 (dd, 1H5 , J¼4, 11 Hz), 3.77 (dd, 1H5 , J¼3, 11 Hz), 2.68 (m, 1H2 ),
0
2.47 (m, 1H2 ), 2.38 (s, 3HMe), 0.91 (d, 18H, t-Bu), 0.10 (d, 12H,
3HAr), 6.52 (t, 1H1 , J¼6 Hz), 4.63 (m, 1H3 ), 4.04 (q, 1H4 , J¼3 Hz),
–Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d: 152.6, 151.1, 143.8, 142.1,
0
0
0
0
0
0
3.90 (dd, 1H5 , J¼4, 11 Hz), 3.75 (dd, 1H5 , J¼3, 11 Hz), 2.68 (m, 1H2 ),
140.4, 134.8, 132.8, 129.3, 118.5, 98.9, 88.2, 84.7, 83.9, 72.1, 62.9, 41.3,
26.1, 25.8, 21.8, 18.5, 18.1, ꢂ4.60, ꢂ4.71, ꢂ5.26, ꢂ5.37. HRMS exact
mass calculated for C31H47N4O3Si2 (MþþH) 579.3108, found
579.3181.
2.47 (m, 1H2 ), 0.90 (d, 18H, t-Bu), 0.08 (d, 12H, –Si((CH3)2)); 13C
0
NMR (75 MHz, CDCl3) d: 152.6,151.2,143.9,141.9,134.9,132.8,129.9,
128.5, 121.6, 98.4, 88.2, 84.7, 84.3, 72.1, 62.9, 41.4, 26.0, 25.8, 18.5,
18.1, ꢂ4.58, ꢂ4.70, ꢂ5.27, ꢂ5.38. HRMS exact mass calculated for
C30H45N4O3Si2 (MþþH) 565.2952, found 565.3030.
4.6.14. 6-((4-Methoxyphenyl)ethynyl)-9-[20-deoxy-30,50-bis-O-
(tert-butyldimethylsilyl)-
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
8.90 (s, 1H2,8), 8.43 (s, 1H2,8), 7.68 (d, 2HAr, J¼9 Hz), 6.90 (d, 2HAr
b-D-erythro-pentofuranosyl]purine (4h)
4.6.9. 6-((2-Methoxyphenyl)ethynyl)-9-[20-deoxy-30,50-bis-O-(tert-
d:
butyldimethylsilyl)-
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
8.91 (s, 1H2,8), 8.43 (s, 1H2,8), 7.65 (d, 1HAr, J¼7.4 Hz), 7.35 (t, 1HAr),
b-D
-erythro-pentofuranosyl]purine (4c)
,
0
0
0
d:
J¼9 Hz), 6.52 (d, 1H1 , J¼6 Hz), 4.63 (m, 1H3 ), 4.03 (q, 1H4 , J¼3 Hz),
0
0
3.87 (dd, 1H5 , J¼4, 11 Hz), 3.83 (s, 3HOMe), 3.77 (dd, 1H5 , J¼3,
0
0
0
0
6.96–6.88 (m, 2HAr), 6.51 (t, 1H1 , J¼6 Hz), 4.64 (m, 1H3 ), 4.02 (q,
11 Hz), 2.68 (m, 1H2 ), 2.46 (m, 1H2 ), 0.89 (d, 18H, t-Bu), 0.09 (d,
1H4 , J¼3 Hz), 3.92 (s, 3HOMe), 3.86 (dd, 1H5 , J¼4, 11 Hz), 3.76 (dd,
12H, –Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d
: 161.0, 152.6, 151.0,
0
0
0
0
0
1H5 , J¼3, 11 Hz), 2.66 (m, 1H2 ), 2.45 (m, 1H2 ), 0.89 (d, 18H, t-Bu),
143.7, 142.2, 134.6, 127.1, 114.2, 113.5, 99.1, 88.2, 84.6, 83.7, 72.1, 62.9,
55.4, 41.3, 26.1, 25.9, 18.5, 18.1, ꢂ4.60, ꢂ4.70, ꢂ5.27, ꢂ5.37. HRMS
exact mass calculated for C31H47N4O4Si2 (MþþH) 595.3058, found
595.3124.
0.06 (d, 12H, –Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d
: 161.1, 152.5,
151.1, 143.8, 142.2, 134.8, 134.6, 131.6, 120.5, 110.9, 110.8, 95.5, 88.2,
84.6, 72.0, 62.8, 56.0, 41.3, 26.0, 25.8, 18.5, 18.1, ꢂ4.62, ꢂ4.72, ꢂ5.28,
ꢂ5.38. HRMS exact mass calculated for C31H47N4O4Si2 (MþþH)
595.3058, found 595.3123.
Acknowledgements
4.6.10. 6-(Naphthalene-1-ylethynyl)-9-[20-deoxy-30,50-bis-O-(tert-
We acknowledge the generous support of Grand Valley State
University through its Summer Student Scholars Program (the
award of an S3 grant to F.N.N. and E.A.L.). We also thank the
Chemistry Department at GVSU for providing financial support,
through the Weldon Fund to B.E.H. The constructive comments of
the referees are gratefully acknowledged.
butyldimethylsilyl)-
b-D-erythro-pentofuranosyl]purine (4d)
Prepared by general procedure C. 1H NMR (300 MHz, CDCl3)
d:
8.99 (s, 1H2,8), 8.67 (d, 1HAr, J¼8.5 Hz), 8.52 (s, 1H2,8), 8.01–7.87 (m,
0
3HAr), 7.66 (m,1HAr), 7.58–7.47 (m, 2HAr), 6.55 (t,1H1 , J¼6.3 Hz), 4.66
0
0
0
(m, 1H3 ), 4.06 (q, 1H4 , J¼3 Hz), 3.89 (dd, 1H5 , J¼4, 11 Hz), 3.80 (dd,
0
0
0
1H5 , J¼3, 11 Hz), 2.70 (m, 1H2 ), 2.49 (m, 1H2 ), 0.92 (d, 18H, t-Bu),
0.10 (d, 12H, –Si((CH3)2)); 13C NMR (75 MHz, CDCl3)
d
: 152.6, 151.2,
Supplementary data
144.0,142.0,139.9,137.2,135.2,133.6,133.2,132.3,130.6,128.4,127.5,
129.8, 126.5, 125.2, 119.2, 96.9, 89.2, 88.2, 84.7, 71.9, 62.8, 41.4, 26.1,
25.8, 18.5, 18.1, ꢂ4.59, ꢂ4.69, ꢂ5.26, ꢂ5.36. HRMS exact mass cal-
culated for C34H47N4O3Si2 (MþþH) 615.3108, found 615.3209.
General experimental procedures and characterization data for
all new products (1H and 13C NMR, HRMS, and GC–MS). This ma-
terial is available via the Internet at www.sciencedirect.com.

F.N. Ngassa et al. / Tetrahedron 65 (2009) 4085–4091
4091
9. Silva, S.; Sylla, B.; Suzenet, F.; Tatiboue¨t, A.; Rauter, A. P.; Rollin, P. Org. Lett.
2008, 10, 853.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.03.064.
10. For selected examples of Sonogashira cross-coupling under Cu-free conditions,
see: (a) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Synthesis 2005, 804; (b) Gholap, A. R.;
Venkatesan, K.; Pasricha, R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem.
2005, 70, 4869; (c) Kim, J.-H.; Lee, D.-H.; Jun, B.-H.; Lee, Y.-S. Tetrahedron Lett.
2007, 48, 7079; (d) Ljungdahl, T.; Bennur, T.; Dallas, A.; Emtena¨s, H.;
Mårtensson, J. Organometallics 2008, 27, 2490.
References and notes
1. For selected references on alkynes in natural products, see: (a) Banthorpe, D. V.
In Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; Wiley: New York,
NY, 1994; pp 689–737; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4442; (c) Giese, M. W.; Moser, W. H. J. Org. Chem. 2005, 70,
6222; (d) Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689; (e) Hong, B.-C.;
Nimje, R. Y. Curr. Org. Chem. 2006, 10, 2191; (f) Niess, B.; Hartung, I. V.; Haustedt,
L. O.; Hoffmann, H. M. R. Eur. J. Org. Chem. 2006, 1132; (g) Hamajima, A.; Isobe,
M. Org. Lett. 2006, 8, 1205.
´
`
11. Beauperin, M.; Fayad, E.; Amardeil, R.; Cattey, H.; Richard, P.; Brandes, S.;
Meunier, P.; Hierso, J.-C. Organometallics 2008, 27, 1506.
12. For selected examples of Sonogashira cross-coupling under Ligand-free
conditions, see: (a) Li, P.; Wang, L.; Li, H. Tetrahedron Lett. 2005, 61, 8633; (b)
Gil-Molto´, J.; Na´jera, C. Eur. J. Org. Chem. 2005, 4073; (c) Zhang, G. Synlett
2005, 619.
13. Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391.
14. Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett.
2008, 10, 945.
15. Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan, P. Bioorg. Med.
Chem. Lett. 1999, 9, 1063.
16. Verdugo, D. E.; Cancilla, M. T.; Ge, X.; Gray, N. S.; Chang, Y.-T.; Schultz, P. G.;
Negishi, M.; Leary, J. A.; Bertozzi, C. R. J. Med. Chem. 2001, 44, 2683.
17. Perez, O. D.; Chang, Y.-T.; Rosania, G.; Sutherlin, D.; Schultz, P. G. Chem. Biol.
2002, 9, 475.
2. For selected papers on the original Sonogashira reactions, see: (a) Sonogashira,
K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 44, 4467; (b) Sonogashira, K.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 3, p 521; (c) Sonogashira, K. J. Organomet. Chem. 2002, 653,
46; (d) Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-Interscience: New York, NY,
2002; p 493; (e) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., de Meijera, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, p 319.
3. For recent reviews on the Sonogashira cross-coupling reactions, see: (a)
Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1879; (b) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079; (c) Chinchilla, R.; Na´jera, C.
Chem. Rev. 2007, 107, 874.
4. Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
5. For selected papers on palladium-catalyzed homocoupling reactions of alkynes,
see: (a) Kotora, M.; Takahashi, T. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-Interscience: New
York, NY, 2002; p 973; (b) Liang, Y.; Xie, Y.-X.; Li, J.-H. J. Org. Chem. 2006, 71, 379
and references cited therein.
ˇ
18. Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto,
M. J. J. Med. Chem. 2005, 48, 5869.
19. Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917.
20. Firth, A. G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C. G. Tetrahedron Lett. 2006,
47, 3529.
21. Crisp, G. T.; Gore, J. Tetrahedron 1997, 53, 1523.
22. Lakshman, M. K. Curr. Org. Synth. 2005, 2, 83.
23. Nagy, A.; Kotschy, A. Tetrahedron Lett. 2008, 49, 3782.
24. Ngassa, F. N.; DeKorver, K. A.; Melistas, T. S.; Yeh, E. A.-H.; Lakshman, M. K. Org.
Lett. 2006, 8, 4613.
25. Gunda, P.; Russon, L. M.; Lakshman, M. K. Angew. Chem., Int. Ed. 2004, 43, 6372.
26. Sørensen, U. S.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697.
27. Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am. Chem. Soc. 1999,
121, 6090.
6. Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org.
Chem. 2007, 72, 2053.
7. Dı´az-Sa´nchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Ferna´ndez, R.; Juaristi, E.
J. Org. Chem. 2007, 72, 4822.
8. Mehta, P. V.; Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 10, 1147.