Palladium(II) chloride and a (dipyridin-2-ylmethyl)amine-derived palladium(II) chloride complex as highly efficient catalysts for the synthesis of alkynes in water or in NMP and of diynes in the absence of reoxidant

Article abstract of DOI:10.1002/ejoc.200500319

The (dipyridin-2-ylmethyl)amine-derived palladium chloride complex 1 and PdCl₂ are efficient catalysts for cross-coupling reactions between terminal alkynes and aryl iodides or bromides under modified Sonogashira-Cassar-Heck conditions. The alkynylation can be performed under copper-free conditions in water at reflux or at room temperature under air with pyrrolidine as base and tetra-n-butylammonium bromide (TBAB) as additive, with TONs of up to 7 × 10⁴ and TOFs (h^-1) of up to 6666. Terminal alkynes can be arylated in NMP as well under copper- and amine-free conditions at 110°C or room temperature, with tetra-n-butylammonium acetate (TBAA) acting as base with TONs up to 2 × 10⁵ and TOFs (h ^-1) up to 66 666. In general, complex 1 displays a slightly higher efficiency than PdCl₂ as catalyst and maintains the same activity after five consecutive runs. Alternatively, these alkynylation processes can be carried out under microwave heating conditions. The homocoupling of terminal alkynes to the corresponding 1,3-diynes proceeds under phosphane-free conditions with the (dipyridin-2-yrmethyl)amine-derived palladium chloride complex 1 or with PdCl₂ as catalysts and with CuI as cocatalyst in NMP with use of either TBAA or pyrrolidine as bases. This Glaser-type reaction can be performed at 110°C or at room temp. in the presence of air without the use of a reoxidant. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500319

FULL PAPER
Palladium(II) Chloride and a (Dipyridin-2-ylmethyl)amine-Derived
Palladium(II) Chloride Complex as Highly Efficient Catalysts for the Synthesis
of Alkynes in Water or in NMP and of Diynes in the Absence of Reoxidant
Juan Gil-Moltó[a] and Carmen Nájera*[a]
Keywords: Palladium catalyst / N ligands / Alkynes / Diynes / Water chemistry
The (dipyridin-2-ylmethyl)amine-derived palladium chloride
complex 1 and PdCl2 are efficient catalysts for cross-coupling
reactions between terminal alkynes and aryl iodides or bro-
mides under modified Sonogashira–Cassar–Heck conditions.
The alkynylation can be performed under copper-free condi-
tions in water at reflux or at room temperature under air with
pyrrolidine as base and tetra-n-butylammonium bromide
(TBAB) as additive, with TONs of up to 7×104 and TOFs
(h–1) of up to 6666. Terminal alkynes can be arylated in NMP
as well under copper- and amine-free conditions at 110 °C
or room temperature, with tetra-n-butylammonium acetate
(TBAA) acting as base with TONs up to 2×105 and TOFs
(h–1) up to 66666. In general, complex 1 displays a slightly
higher efficiency than PdCl2 as catalyst and maintains the
same activity after five consecutive runs. Alternatively, these
alkynylation processes can be carried out under microwave
heating conditions. The homocoupling of terminal alkynes to
the corresponding 1,3-diynes proceeds under phosphane-
free conditions with the (dipyridin-2-ylmethyl)amine-derived
palladium chloride complex 1 or with PdCl2 as catalysts and
with CuI as cocatalyst in NMP with use of either TBAA or
pyrrolidine as bases. This Glaser-type reaction can be per-
formed at 110 °C or at room temp. in the presence of air with-
out the use of a reoxidant.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
came more popular over the years.[7] Recent improvements
in the alkynylation reaction have been concentrated on the
simpler Cassar–Heck protocol, the elimination of copper
as co-catalyst and the amine as solvent, in order to avoid
undesired homocoupling by-reactions, and the precipitation
of catalytically inactive palladium black.[9]
Introduction
Palladium-catalysed homo-[1] and cross-coupling[2] reac-
tions are very important processes in modern acetylene
chemistry for the synthesis of natural products and biolo-
gically active molecules, and in materials science for the
preparation of conjugated acetylenic oligomers and poly-
mers, liquid crystals and other engineering materials.[3]
These reactions are widely used for the synthesis of sym-
metrical 1,3-diynes and internal alkynes or enynes. Several
important aspects have been improved in recent years,
mainly concerning the elimination of the reoxidant in the
case of the Pd–Cu co-catalysed homocoupling of terminal
alkynes.[4] Palladium-catalysed cross-coupling reactions of
aryl or vinyl halides and terminal alkynes were first re-
ported by Cassar’s,[5] Heck’s[6] and Sonogashira’s[7] groups.
The first two of these groups worked under copper-free
conditions using either sodium methoxide as base and
DMF as solvent[5] or an amine as both base and solvent,[6]
respectively. Later, it was found that the reaction was faster
in pyrrolidine as solvent.[8] However, the copper-co-cata-
lysed reaction conditions in an amine as solvent have be-
The use of water as solvent represents one of the safest
and economically and environmentally most advantageous
alternatives to organic solvents for metal-catalysed reac-
tions.[10] Aqueous-phase Sonogashira couplings have been
performed with the aid of hydrophilic phosphines,[11] poly-
mer-supported ligands,[12] palladium on carbon,[13] palla-
dium zeolites[14] and other activating reagents such as proli-
nol,[15] potassium fluoride,[16] aqueous ammonia[17] and
quaternary ammonium salts.[18] Sonogashira couplings in
neat water with use of (PPh3)2PdCl2,[19] (PPh3)4Pd[20] and
palladium-phosphinous acid[21] as catalysts have been de-
scribed. Microwave-assisted transition metal-free alkynyl-
ation reactions in water have been recently achieved, show-
ing limited scope.[22] We reported the first cross-coupling
reactions between terminal alkynes and aryl halides in neat
water under copper-free conditions with use of a (dipyridin-
2-ylmethyl)amine-derived palladium dichloride complex
1
[23] as catalyst.[24] We now report a full account of the cata-
[a] Departamento de Química Orgánica, Facultad de Ciencias, and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
lytic activity of complex 1 and ligandless PdCl2 in cross-
coupling and homocoupling reactions of terminal alkynes
in water and in NMP (N-methylpyrrolidone) as solvents.
Fax: +34-965903549
E-mail: cnajera@ua.es
Eur. J. Org. Chem. 2005, 4073–4081
DOI: 10.1002/ejoc.200500319
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4073

J. Gil-Moltó, C. Nájera
FULL PAPER
(2 equiv.) as base the yield increased again, to 93% after
6 h, whereas in the presence of tetra-n-butylammonium
bromide (TBAB, 0.5 equiv.) the reaction had taken place
quantitatively after 1 h (Table 1, Entries 4 and 5). Under the
last set of reaction conditions the formation of secondary
products was almost inhibited, and the loading of complex
1 could be reduced to 0.01 mol-% with similar results
(Table 1, compare Entries 5 and 7). Under these reaction
conditions, complex 1 and ligandless palladium dichlo-
ride[24] (0.01 mol-% of Pd) gave the same results and the
amount of enynes was less than 4% (Table 1, compare En-
tries 7 and 8). With a low loading of complex 1 (0.001 mol-
%) the reaction was slower (4 d) and a 3:1 mixture of alkyne
2a and enynes was obtained (Table 1, Entry 9). Alterna-
tively, the alkynylation reaction could be performed at room
temperature in ca. 1 d by increasing the loading of catalysts
to 1 mol-%. Under these reaction conditions, complex 1
showed a higher efficiency than PdCl2 (Table 1, compare
Entries 10 and 11). Cross-coupling between phenylacetylene
and 4-chlorophenyl bromide was performed in water at re-
flux with pyrrolidine as base and TBAB as additive in the
presence of 0.2 mol-% of palladium. In this alkynylation
process complex 1 was the best catalyst, PdCl2 providing a
lower yield together with a 6:1 mixture of alkyne 2a and
the trans/cis-enyne resulting from the head-to-head dimer-
ization of phenylacetylene[27] (Table 1, compare Entries 12
and 13). Alternatively, alkynylation of 4-chloroiodobenzene
and 4-chlorobromobenzene with phenylacetylene could also
be carried out under microwave irradiation conditions at
120 °C, requiring 5 and 10 min, respectively (Table 1, En-
tries 6 and 14).
Results and Discussion
Cross-Coupling Reactions between Aryl Halides and
Terminal Alkynes
The reaction conditions for the alkynylation of 4-chlo-
rophenyl iodide and bromide with phenylacetylene in neat
water were studied with the dipyridine–palladium dichlo-
ride complex 1[25] and palladium dichloride as catalysts
(Scheme 1 and Table 1). In a first round of screening, dif-
ferent bases and additives were essayed for the coupling be-
tween 4-chlorophenyl iodide and phenylacetylene to give al-
kyne 2a in the presence of 0.1 mol-% of complex 1 as cata-
lyst in water at reflux (Table 1, Entries 1–5). When K2CO3
was used as base in the presence of tetra-n-butylammonium
acetate (TBAA, 1 equiv.) and with pyrrolidine (5 mol-%),
the coupling had taken place in high yields after 7 h
(Table 1, Entries 1 and 2), whereas a mixture of K2CO3 and
5 mol-% of pyrrolidine afforded a lower yield (Table 1, En-
try 3). In all these cases the formation of small amounts of
1,4-diphenylbuta-1,3-diyne (3a) (up to 4%) and other sec-
ondary products such as enynes[26] from the excess of phen-
ylacetylene (up to 19%) were observed. When the cross-
coupling reaction was performed with only pyrrolidine
Scheme 1.
Table 1. Optimization of the reaction conditions for the cross-coupling between phenylacetylene and 4-chlorophenyl iodide or bromide
in water.
Product ratio[b]
2a/3a/enynes
Entry
X
Catalyst (mol-%)
Base (2 equiv.)
Additive
T [°C]
Time
Yield [%][a]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
1 (0.1)
K2CO3
K2CO3
K2CO3
TBAA[c]
100
100
100
100
100
120[f]
100
100
100
25
7 h
7 h
5 h
6 h
96
100
69
93
100 (91)
96
100 (93)
100
70
94 (89)
69
84:3:13
90:0:10
80:1:19
90:1:9
97:0:3
84:0:16
96:0:4
97:0:3
76:0:24
97:0:3
100:0:0
94:4:2
86:0:14
75:0:25
1 (0.1)
TBAA[c][d]
[d]
1 (0.1)
-
1 (0.1)
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
-
1 (0.1)
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
TBAB[e]
1 h
1 (0.1)
5 min
1.5 h
1.5 h
4 d
1 d
1 d
4 h
2.5 h
10 min
1 (0.01)
PdCl2 (0.01)
1 (0.001)
1 (1)
9
10
11
12
13
14
PdCl2 (1)
1 (0.2)
PdCl2 (0.2)
1 (0.1)
25
100
100
120[f]
96 (82)
73
66
[a] GC yields for compound 2a based on aryl halide (numbers in parenthesis are isolated yields of alkyne 2a after column chromatog-
raphy). [b] Determined by GC. [c] 1 equiv. [d] Pyrrolidine (5 mol-%) was added. [e] 0.5 equiv. [f] The reaction was carried out under
microwave irradiation conditions.
4074
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4073–4081

A (Dipyridin-2-ylmethyl)amine-Derived Palladium() Chloride Complex
FULL PAPER
The stability of the catalyst 1 in water at reflux and under ing conditions (Table 2, compare Entries 16 and 17). The
aerobic conditions was evaluated by performing the cross- reaction between phenylacetylene and 2-bromothiophene
coupling between 4-chloroiodobenzene and phenylacety- gave place to afford compound 6 in 85% yield in only 2 h
lene in the presence of 0.1 mol-% of complex over several (Table 2, Entry 21). The cross-coupling between (E)-β-bro-
cycles. After the completion of the first run (1 h, 100%), mostyrene and oct-1-yne was performed at room temp. in
new reagents (phenylacetylene, 4-chloroiodobenzene and water over 3 d to afford the enyne 7 stereospecifically in
pyrrolidine) were added to the reaction mixture. Practically 70% yield (Scheme 3).
the same results were obtained after five consecutive runs.
The alkynylation of aryl iodides and bromides under
These aqueous reaction conditions were then applied to copper- and amine-free conditions in the presence of TBAA
cross-coupling reactions between terminal alkynes and elec- as base, NMP as solvent and an oxime-derived palladacycle
tron-poor or electron-rich aryl iodides or bromides to give as catalyst have been described by our group.[4a,9a] We ap-
internal alkynes 2 (Scheme 2 and Table 2). Couplings of 4- plied these conditions to cross-couplings between different
chlorophenyl iodide with phenylacetylene, oct-1-yne and terminal alkynes and aryl iodides or bromides to prepare
(triisopropylsilyl)acetylene took place in short times and alkynes 2 in the presence of complex 1 or PdCl2 as catalysts
with good yields in the presence of 0.01 to 0.1 mol-% of (Scheme 4 and Table 3). Coupling between 4-chloroiodo-
catalyst 1 (Table 2, Entries 1–3). In the case of an arylation- benzene and phenylacetylene was achieved with 0.1 to
reluctant reagent, such as N,N-dimethylpropargylamine, the 0.0005 mol-% loadings of complex 1 in NMP at 110 °C in
reaction proceed with a lower rate and yield (Table 2, En- the presence of 2 equiv. of TBAA in good yields and with
try 4). When the deactivated 4-methoxyphenyl iodide was high rates (Table 3, Entries 1–3). Very high efficiency at
coupled with different terminal alkynes, the results were these very low catalyst loadings was also achieved when
similar to those obtained with the activated 4-chlorophenyl PdCl2 was used as catalyst but the reaction time increased
iodide (Table 2, Entries 5–7). The diarylenediyne 4 was pre- from 3 to 19 h (Table 3, Entry 4). When this reaction was
pared in high yield through the very fast dialkynylation of carried out at room temp. the loadings of both catalysts 1
o-diiodobenzene with phenylacetylene (Table 2, Entry 8). and PdCl2 needed to be increased to 1 mol-% to give 2a in
The alkynylation of N-acetyl-o-iodoaniline was faster with 94% and 95% yields, respectively (Table 2, Entries 5 and 6).
phenylacetylene than with oct-1-yne, affording the corre- In addition, when this coupling was carried out in the pres-
sponding o-alkynylanilides 2h and 2i in 90 and 61% yields, ence of 0.1 mol-% of complex 1 under microwave condi-
respectively (Table 2, Entries 9 and 10). In the former case tions at 120 °C, a quantitative yield was observed after
a concomitant indole cyclization (6% yield) was observed. 5 min reaction time (Table 3, Entry 7).
In the reaction between o-iodophenol and phenylacetylene, Cross-couplings between 4-chloroiodobenzene and (trii-
however, the cyclization took place readily to provide ben- sopropylsilyl)acetylene or N,N-dimethylpropargylamine, to
zofuran 5 as the sole product (Table 2, Entry 11).
give compounds 2c and 2d, respectively, were faster in NMP
than in H2O (Table 3, Entries 8 and 9). When deactivated
4-methoxyiodobenzene was coupled with different terminal
alkynes, higher rates were observed in NMP than in H2O
(Table 3, Entries 10–12). In the case of N,N-dimethylpro-
pargylamine the arylation with 4-methoxyiodobenzene
took place only in NMP, to give product 2n in moderate
yield (Table 3, Entry 13). Similar results were observed in
NMP and in H2O with ortho-substituted iodobenzenes,
which were alkynylated very rapidly to furnish diyne 4, o-
alkynylated acetanilides 2h and 2i and benzofuran 5 in good
yields (Table 3, Entries 14–17).
For cross-couplings of aryl bromides in NMP at 110 °C
in the presence of TBAA as base, 0.1 to 0.2 mol-% loadings
of catalyst 1 were used and the reactions were again faster
than in H2O (Table 3, Entries 18–29). Coupling between
phenylacetylene and 4-chlorobromobenzene to afford al-
kyne 2a was performed with both catalysts for comparison,
giving similar results after 1 h reaction time (Table 3, En-
Scheme 2.
We then studied the cross-coupling reaction with aryl
bromides, using 0.2 to 0.5 mol-% of palladium complex 1
to provide alkynes 2–6 (Table 2, Entries 12–21). In general
these alkynylation reactions took place with lower rates and
yields than those involving aryl iodides. In many cases an
excess of terminal alkyne was added in order to increase
the yield of the expected product 2, due to partial dimeriza-
tion of the terminal alkyne to the corresponding diyne and
enyne. Alternatively, the coupling between phenylacetylene
and 4-methoxyphenyl bromide was performed in a single-
mode microwave cavity in 10 min at 120 °C, giving com-
pound 2e, but in lower yield than under conventional heat-
Scheme 3.
Eur. J. Org. Chem. 2005, 4073–4081
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4075

J. Gil-Moltó, C. Nájera
FULL PAPER
Table 2. Cross-coupling between terminal alkynes and aryl iodides or bromides in water.[a]
[a] Reaction conditions: alkyne (1.2 mmol), aryl halide (1 mmol), pyrrolidine (2 mmol), TBAB (0.5 mmol), complex 1 (0.01–0.5 mol-%),
H2O (2.5 mL) reflux. [b] GC yields for alkynes 2 and 4–6, based on starting aryl halide (numbers in parenthesis are isolated yields after
column chromatography). [c] 2 equiv. were used. [d] A 6% yield of the corresponding indole derivative was obtained. [e] The reaction was
performed under microwave heating conditions (10 min at 120 °C, 0.5 mmol scale).
4076
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4073–4081

A (Dipyridin-2-ylmethyl)amine-Derived Palladium() Chloride Complex
FULL PAPER
Table 3. Cross-coupling of terminal alkynes with aryl iodides and bromides in NMP.[a]
[a] Reaction conditions: alkyne (1.2 mmol), aryl halide (1 mmol), TBAA (2 mmol), complex 1 (0.0005–1 mol-%), NMP (2 mL), 110 °C.
[b] GC yields for alkynes 2, 4–6 based on starting aryl halide (numbers in parenthesis are isolated yields after column chromatography).
[c] The reaction was performed on a 4 mmol scale. [d] The reaction was performed on 15 mmol scale. [e] PdCl2 was used as catalyst. [f] At
room temp. [g] The reaction was performed under microwave heating conditions (5 min at 120 °C, 0.5 mmol scale). [h] 2 equiv. were used.
Eur. J. Org. Chem. 2005, 4073–4081
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4077

J. Gil-Moltó, C. Nájera
FULL PAPER
the case of the alkynylation reactions in NMP. It is worth
noting that we never observed precipitation of palladium
black under the conditions described here for these alkynyl-
ation reactions.
Scheme 4.
It can be concluded that, in general, cross-couplings be-
tween terminal alkynes, specially alkylacetylenes, and aryl
iodides or bromides were more efficient and faster in NMP
than in H2O either with heating or at room temp. Pyrroli-
dine was the base of choice for these alkynylation reactions
in neat water, whereas TBAA was more appropriate for the
NMP couplings. With respect to the palladium catalyst,
both the (dipyridin-2-ylmethyl)amine-derived complex 1
and ligandless PdCl2 can be used for these Sonogashira-
type reactions, but the former catalyst was in general more
efficient. Alternatively, these couplings can be run under
microwave irradiation conditions in shorter reaction times.
tries 18 and 19). Deactivated 4-methoxyphenyl bromide
provided higher yields with alkylacetylenes than with phen-
ylacetylene (Table 3, Entries 23, 25 and 26). For the coup-
ling under microwave conditions to give compound 2e, the
loading of catalyst had to be increased to 0.5 mol-% in or-
der to achieve the same yield as under conventional heating
conditions (Table 3, compare Entries 23 and 24).
The catalytic activity of complex 1 (0.1 mol-%) under
NMP/TBAA conditions was studied as described before in
H2O, but now for coupling between phenylacetylene and 4-
methoxyiodobenzene, always giving quantitative yields of
alkyne 2e after five cycles of 30 min. The same behaviour
was observed for coupling between 4-chlorobromobenzene
and phenylacetylene in the presence of 0.1 mol-% of cata-
lyst 1, with yields between 77 and 81% being obtained dur-
ing five consecutive cycles of 1 h.
The beneficial effect of TBAB as an additive in cross-
couplings between terminal acetylenes and aryl halides in
water can be attributed to the stabilization of palladium
nanoparticles, which can be formed from palladium salts or
complexes in water or in the presence of amines or
alcohols.[28] The formation of palladium nanoparticles by
treatment of a related PS-PEG-anchored dipyridin-2-ylam-
ine–palladium() acetate complex with benzyl alcohol in
water at reflux has been described.[29] A similar reducing
process can take place in the case of complex 1, with the
aid of the amine. In addition, polar organic solvents such
as propylene carbonate and NMP are also able to stabilize
Pd nanoparticles in the absence of surfactants.[28b] We can
Homocoupling Reactions of Terminal Alkynes
For homocoupling of terminal alkynes to give diynes 3
(Scheme 5) we applied the same reaction conditions as we
had found to be appropriate with oxime-derived pallada-
cycles as catalyst.[4a] Homocoupling of alkynes in NMP in
the presence of complex 1 as catalyst and CuI as co-catalyst
in the absence of a reoxidant could be performed either at
110 °C or at room temp. in the presence either of pyrroli-
dine (1.1 equiv.) or of TBAA (1.5 equiv.) as bases, to afford
diynes 3 in high yields (Scheme 5 and Table 4). In general,
therefore postulate that Pd nanoparticles may be formed in Scheme 5.
Table 4. Homocoupling reactions of terminal alkynes to give diynes 3.[a]
Entry
X
Catalyst (mol-%)
Base (2 equiv.)
T [°C]
Time
Yield [%][b]
Product No.
1
2
3
4
5
6
7
8
PhCϵCH
1 (0.05)
PdCl2 (0.05)
1 (0.05)
PdCl2 (0.05)
1 (0.5)
PdCl2 (0.5)
1 (0.5)
PdCl2 (0.5)
0.05
0.05
0.5
0.5
0.05
0.05
0.5
0.05
0.05
0.5
0.5
TBAA
TBAA
pyrrolidine
pyrrolidine
TBAA
110
110
110
110
rt
rt
rt
4 h
6 h
2 h
2 h
22 h
8 d
2 h
2 h
21.5 h
3 h
19 d
9 d
1 d
3 h
2.5 h
5 h
2 h
4 d
3.5 h
100 (99)
94
100
100
100
28
92
98
100 (92)
100
100
100 (92)
-
100 (82)
63
99 (90)
98
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3j
TBAA
pyrrolidine
pyrrolidine
TBAA
pyrrolidine
TBAA
pyrrolidine
TBAA
pyrrolidine
pyrrolidine
TBAA
rt
9
nC6H13CϵCH
110
110
rt
10
11
12
13
14
15
16
17
18
19
rt
iPr3SiCϵCH
110
110
rt
110
110
rt
cC6H11CϵCH
pyrrolidine
TBAA
pyrrolidine
3j
100
91
3j
3j
rt
[a] Reaction conditions: alkyne (1 mmol), pyrrolidine (1.1 mmol) or TBAA (1.5 mmol), complex 1 or PdCl2, CuI (5 mol-%), NMP (2 mL)
110 °C or room temp. [b] GC yields for compounds 3 based on starting alkyne (numbers in parenthesis are isolated yields of diyne 3
after column chromatography).
4078
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4073–4081

A (Dipyridin-2-ylmethyl)amine-Derived Palladium() Chloride Complex
FULL PAPER
(0.040–0.063 mm, Merck). Thin layer chromatography was per-
formed on Polygram® SIL G/UV254 plates. M.p.s were determined
on a Reichert Thermovar apparatus. Gas chromatographic analyses
were performed on a HP-6890 instrument fitted with a WCOT HP-
1 fused silica capillary column. IR data were collected on a Nicolet
Impact-400D-FT spectrophotometer in cm–1. 1H NMR spectra
were recorded on a Bruker AC 300 instrument (300 MHz). Chemi-
cal shifts are reported in ppm with tetramethylsilane (TMS,
0.00 ppm) as internal standard. 13C NMR spectra were recorded
at 75 MHz with CDCl3 as the internal reference. EI-MS were mea-
the reaction was performed at 110 °C with 0.05 mol-% of
complex 1 or PdCl2 and with 0.5 mol-% loading of palla-
dium at room temp. With regard to the use of pyrrolidine
or TBAA as bases, the former gave higher rates, especially
at room temp. In the case of (triisopropylsilyl)acetylene,
homocoupling to give diyne 3c took place only in the pres-
ence of pyrrolidine as base (Table 4, Entries 13–15). With
respect to the catalyst, complex 1 and PdCl2 displayed sim-
ilar efficiencies with pyrrolidine as base (Table 4, Entries 3,
4 and 7, 8), but complex 1 proved to be the more efficient sured on an Agilent Technologies 5973N Mass Selective Detector
G2579A in m/z (rel. intensity in % of base peak). HRMS were
performed on a Finnigan MAT95S apparatus. Elemental analysis
were carried out in a Carlo Erba EA 1108 (CHNS-O) by the corre-
sponding services at the University of Alicante. The catalysts were
weighed in an electronic microscale (Sartorius, XM1000P) with a
precision of 1 µg. Microwave reactions were performed with a
CEM Discover Synthesis Unit in glass vessels (10 mL) sealed with
a septum under magnetic stirring at 120 °C and 120 W.
catalyst when TBAA was used as base (Table 4, Entries 1,
2 and 5, 6). Under aerobic conditions, the oxygen present
in the reaction mixture was enough to act as an oxidant of
CuI to CuII.[30] However, these Glaser-type homocouplings
failed in water as solvent. When the homocoupling of phen-
ylacetylene was performed under microwave irradiation
conditions at 120 °C, either in a sealed tube or in a open
vessel, the corresponding enyne was mainly formed.
General Procedure for Cross-Couplings of Aryl Halides with Alkynes
in Water: A 10 mL round-bottomed flask was charged with palla-
dium catalyst 1 or PdCl2 (see Tables 1 and 2), aryl halide (1 mmol),
alkyne (1.5 mmol), pyrrolidine (2 mmol), tetrabutylammonium
bromide (0.5 mmol) and water (2.5 mL). The mixture was stirred
at 100 °C or room temp. for the reaction time indicated in Tables 1
and 2. The reaction progress was analysed by GLC. The mixture
was extracted with EtOAc (3×15 mL), dried over MgSO4, concen-
trated in vacuo and purified by flash chromatography on silica gel.
Conclusions
In conclusion, both the (dipyridin-2-ylmethyl)amine-de-
rived palladium() chloride complex 1 and PdCl2 have been
demonstrated to be very active and efficient catalysts for
the copper-free alkynylation of aryl iodides and bromides
in water at reflux and at room temp. in the presence of
pyrrolidine as base and TBAB as additive. Complex 1
showed higher efficiency than PdCl2, especially under room
temp. conditions. Alternatively, cross-couplings between
General Procedure for Cross-Couplings of Aryl Halides with Alkynes
in NMP: A mixture of palladium catalyst 1 or PdCl2 (see Table 3),
aryl halide (1 mmol), alkyne (1.5 mmol) and tetrabutylammonium
acetate (2 mmol) in NMP (2 mL) was stirred at 110 °C or room
terminal alkynes and aryl iodides or bromides can be per- temp. for the reaction time indicated in Table 3. The reaction pro-
gress was analysed by GLC. The reaction mixture was extracted
with water and EtOAc, dried over MgSO4, concentrated in vacuo
and purified by flash chromatography on silica gel.
formed under copper- and amine-free conditions, either
with complex 1 or PdCl2, in NMP as solvent at 110 °C with
TBAA as base. The efficiency of these cross-coupling pro-
cesses was higher in NMP (TOFs up to 66666 h–1) than in
water (TOFs up to 6666 h–1). Complex 1 showed very high
stability in water and in NMP under aerobic conditions and
no deactivation was observed after five consecutive cycles.
These alkynylation reactions can also be performed under
MW conditions at 120 °C, with reaction times of 5 to
10 min. For the homocoupling reaction to prepare diynes,
NMP had to be used as solvent and complex 1 was the
more efficient catalyst, especially at room temp., the reac-
tion failing with water as solvent. These Glaser-type reac-
tions must be carried out in the presence of CuI as co-cata-
lyst but in the absence of a reoxidant, just working under
aerobic conditions. The use of pyrrolidine as base afforded
higher reaction rates than TBAA either at 110 °C or at
room temp. All these results indicate that the designed pyri-
dine ligand could be a good candidate for inmobilization
on a solid support in order to recover the palladium after
the coupling.
Compounds 2a, 2e, 2h, 2k, 2l, 2m, 4, 5 and 6 are commercially
available, while compounds 2b,[4a] 2c,[4a] 2d,[31] 2f,[32] 2g,[4a] 2n[33]
and 7[34] have been reported previously and were characterized by
comparison with their reported data. Physical, analytical and spec-
troscopic data of newly synthesized compounds follow:
N-[2-(1-Octynyl)phenyl]acetamide (2i): Colourless solid, m.p. 62 °C.
Rf (Hex/AcOEt 9:1) = 0.25. 1H NMR (CDCl3): δ = 8.37 (d, J =
8.3 Hz, 1 H,), 7.96 (br. s, 1 H), 7.37 (dd, J1 = 1.2, J2 = 7.6 Hz, 1
H), 7.29–7.24 (dt, J1 = 1.23, J2 = 8.8 Hz, 1 H), 6.99 (t, J = 7.5 Hz,
1 H), 2.50 (t, J = 6.9 Hz, 2 H), 2.20 (s, 1 H), 1.69–1.60 (m, 2 H),
1.53–1.44 (m, 2 H), 1.35–1.31 (m, 4 H), 0.91 (t, J = 6.9 Hz, 3
H) ppm. 13C NMR (CDCl3): δ = 168 (C=O), 138.8, 313.4, 128.7,
123.1, 118.9, 112.5 (6×C-Ar), 97.8, 75.9 (2×CϵC), 31.3 (CH2),
28.6 (2×CH2), 24.8 (CH3), 22.5, 19.5 (2×CH2), 14.0 (CH3) ppm.
IR (KBr): ν = 3259.34, 3050, 2962.06, 2930.66, 2856.06, 2235.51,
˜
1663.94, 1576.69, 1536.55, 1447.37, 1365.88, 1304.44, 756.52, 725.6,
689.69 cm–1. EIMS (70 eV): m/z (%) = 243 [M]+ (18), 200 (29), 186
(33), 173 (33), 172 (36), 158 (23), 143.9 (29), 142.9 (23), 129.9 (100),
116.9 (18), 114.9 (15), 105.9 (27), 102.9 (21), 76.9 (21). HRMS
calcd. 243.1623, found 243.1635. C16H21NO (243.3): calcd. C
78.97, H 8.70, N 5.76; found C 79.05, H 8.76, N 5.73.
1-(4-Chlorophenyl)-2-cyclohexylacetylene (2j): Yellow oil, Rf (Hex)
= 0.61. H NMR (CDCl3): δ = 7.29 (d, J = 8.6 Hz, 2 H), 7.21 (d,
Experimental Section
1
General Methods: The reagents and solvents were obtained from
commercial sources and were generally used without further purifi-
cation. Flash chromatography was performed on silica gel 60
J = 8.6 Hz, 2 H), 2.59–2.51 (m, 1 H), 1.87–1.72 (m, 4 H), 1.55–
1.49 (m, 3 H), 1.33–1.29 (m, 3 H) ppm. 13C NMR (CDCl3): δ =
133.2, 132.7, 128.3, 122.6 (6×C–Ar), 95.4, 79.4 (2×CϵC), 32.5
Eur. J. Org. Chem. 2005, 4073–4081
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4079

J. Gil-Moltó, C. Nájera
FULL PAPER
[4]
a) D. A. Alonso, C. Nájera, M. C. Pacheco, Adv. Synth. Catal.
2003, 345, 1146–1158; b) A. S. Batsanov, J. C. Collins, I. J. S.
Fairlamb, J. P. Holland, J. A. K. Howard, Z. Lin, T. B. Marder,
A. C. Parsons, R. M. Ward, J. Zhu, J. Org. Chem. 2005, 70,
703–706.
L. Cassar, J. Organomet. Chem. 1975, 93, 253–257.
H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259–
263.
K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470.
M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993,
34, 6403–6406.
(CH ), 29.5 (CH), 25.8 (CH ), 25.3 (CH ) ppm. IR (film): ν =
˜
2
2
2
2931.45, 2853.96, 2667.07, 2235.51, 1489.71, 1448.35, 1397.53,
1090.95, 1014.54, 827.29 cm–1. EIMS (70 eV): m/z (%) = 220 [M +
2] (30), 219 (15), 218 [M]+ (93), 190.9 (20), 189.9 (34), 183 (41),
176.9 (32), 175.9 (27), 174.9 (69), 163.9 (31), 161.9 (36), 155 (55),
154 (31), 153 (34), 152 (22), 150.9 (17), 148.9 (32), 142 (28), 141
(100), 138.9 (24), 137.9 (18), 135.9 (37), 129 (48), 128 (21), 126.9
(51), 126 (21), 124.9 (24), 115 (24). HRMS calcd.218.0862, found
218.0859.
[5]
[6]
[7]
[8]
[9]
1-(2-Cyclohexyl-1-ethynyl)-4-methoxybenzene (2o): Yellow oil, Rf
(Hex) = 0.24. 1H NMR (CDCl3): δ = 7.24 (d, J = 8.7 Hz, 2 H),
6.71 (d, J = 8.7 Hz, 2 H), 3.69 (s, 3 H), 2.51–2.43 (m, 1 H), 1.81–
1.24 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 158.9, 132.8, 116.2,
113.7 (6×C–Ar), 92.8, 80.1 (2×CϵC), 55.1 (OCH3), 32.8 (CH2),
a) D. A. Alonso, C. Nájera, M. C. Pacheco, Tetrahedron Lett.
2002, 43, 9365–9368; b) D. Gelman, S. L. Buchwald, Angew.
Chem. Int. Ed. 2003, 42, 5993–5996; c) D. Mery, K. Heuzé,
D. Astruc, Chem. Commun. 2003, 1934–1935; d) A. Soheili, J.
Albaneze-Walker, J. A. Murry, P. G. Dormer, D. L. Hughes,
Org. Lett. 2003, 5, 4191–4194; e) K. Heuzé, D. Mery, D. Gauss,
D. Astruc, Chem. Commun. 2003, 2274–2275; f) Y. Ma, C.
Shong, W. Jiang, Q. Wu, Y. Wang, X. Liu, M. S. Andrus, Org.
Lett. 2003, 5, 3317–3319; g) A. Arques, D. Aunon, P. Molina,
Tetrahedron Lett. 2004, 45, 4337–4340; h) S. Park, M. Kim,
D. H. Koo, S. Chang, Adv. Synth. Catal. 2004, 346, 1638–1640;
i) S. Rau, K. Lamm, H. Görls, J. Schöffel, D. Walther, J. Or-
ganomet. Chem. 2004, 689, 3582–3592; j) J. Cheng, Y. Sun, F.
Wang, M. Guo, J.-H. Xu, Y. Pan, Z. Zhang, J. Org. Chem.
2004, 69, 5428–5432; k) S. Urgaonkar, J. G. Verkade, J. Org.
Chem. 2004, 69, 5752–5755; l) M. Feuerstein, H. Doucet, M.
Santelli, Tetrahedron Lett. 2004, 45, 8443–8446; m) E. Tyrrell,
A. Al-Saardi, J. Millet, Synlett 2005, 487–488.
a) A. Lubineau, J. Auge, in: Modern Solvents in Organic Syn-
thesis (Ed.: P. Knochel), Springer, Berlin, 1999; b) Organic Syn-
thesis in Water (Ed.: P. A. Grieco), Blackie Academic & Profes-
sional, London, 1998; c) Aqueous-Phase Organometallic Catal-
ysis, Concepts and Applications (Eds.: B. Cornils, W. A. Herrm-
ann), Wiley-VCH, Weinheim, 1998; d) C.-J. Li, T.-H. Chen,
Organic Reactions in Aqueous Media, Kluwer Academic Pub-
lishers, Dordrecht, 1997.
a) A. L. Casalnuovo, J. C. Calabrese, J. Am. Chem. Soc. 1990,
112, 4324–4330; b) J. P. Genêt, E. Blart, M. Savignac, Synlett
1992, 715–717; c) C. Amatore, E. Blart, J. P. Genêt, A. Jutand,
S. Lemaire-Audoire, M. Savignac, J. Org. Chem. 1995, 60,
6829–6839; d) H. Dibowski, F. P. Schmidtchen, Tetrahedron
Lett. 1998, 39, 525–529; e) H. Dibowski, F. P. Schmidtchen,
Angew. Chem. Int. Ed. 1998, 37, 476–478; f) D. T. Bong, M. R.
Ghadiri, Org. Lett. 2001, 3, 2509–2511; g) E. Genin, R. Amen-
gual, V. Michelet, M. Savignac, A. Jutand, L. Neuville, J. P.
Genêt, Adv. Synth. Catal. 2004, 346, 1733–1741; h) R. B. De-
Vasher, L. R. Moore, K. H. Shaughnessy, J. Org. Chem. 2004,
69, 7919–7927.
a) D. E. Bergbreiter, Y.-S. Liu, Tetrahedron Lett. 1997, 38,
7843–7846; b) Y. Uozumi, Y. Kobayashi, Heterocycles 2003, 59,
71–74.
M. P. López-Deber, L. Castedo, J. R. Granja, Org. Lett. 2001,
3, 2823–2826.
L. Djakovitch, P. Rollet, Tetrahedron Lett. 2004, 45, 1367–1370.
M. Pal, V. Subramanian, K. Parasuraman, K. R. Yeleswarapu,
Tetrahedron 2003, 59, 9563–9570.
L. Wang, P. Li, Synth. Commun. 2003, 33, 3679–3685.
M. S. M. Ahmed, A. Mori, Tetrahedron 2004, 60, 9977–9982.
a) R. Rossi, A. Carpita, M. G. Quirici, M. L. Gaudenzi, Tetra-
hedron 1982, 38, 631–637; b) A. Carpita, A. Lessi, R. Rossi,
Synthesis 1984, 571–572; c) R. Rossi, A. Carpita, A. Lezzi, Tet-
rahedron 1984, 40, 2773–2779; d) J.-F. Nguefack, V. Bolitt, D.
Sinou, Tetrahedron Lett. 1996, 37, 5527–5530.
29.6 (CH), 25.9 (CH ), 24.9 (CH ) ppm. IR (film): ν = 2931.04,
˜
2
2
2853.42, 2235.5, 1606.29, 1509.29, 1447.8, 1286.84, 1250.96,
1172.02, 1105.21, 1033.83, 830.72 cm–1. EIMS (70 eV): m/z (%) =
215 (16), 214 [M]+ (100), 172 (25), 172 (78), 144.9 (19), 142.9 (17),
141 (17), 127.9 (24), 121 (16) 114.9 (30). HRMS calcd. 214.1358,
found 214.1356.
General Procedure for Homocouplings of Terminal Alkynes: A mix-
ture of palladium catalyst 1 or PdCl2 (see Table 4), alkyne
(1 mmol), tetra-n-butylammonium acetate (1.5 mmol) or pyrroli-
dine (1.1 mmol) in NMP (2 mL) was heated to 110 °C or at room
temp. in air for the reaction time shown in Table 4. The reaction
progress was analysed by GLC. The mixture was extracted with
water and EtOAc, dried over MgSO4, concentrated in vacuo and
purified by flash chromatography on silica gel. Compound 3a is
commercially available, and compounds 3b,[4a] 3c[4a] and 3j[35] have
been reported previously and were characterized by comparison
with their reported data.
[10]
[11]
Acknowledgments
This work was supported by the Dirección General de Investiga-
ción of the Ministerio de Educación y Ciencia (MEC) (grants:
BQU2001–0724-CO2–01, CTQ2004–00808/BQU) and the Univer-
sity of Alicante. J. G.-M. thanks the MEC for a predoctoral fellow-
ship.
[1] For recent reviews on Glaser-type reactions, see: a) M. Kotora,
T. Takahashi, in: Handbook of Organopalladium Chemistry for
Organic Synthesis (Eds.: E. Negishi, A. de Meijere), Wiley-In-
terscience, New York, 2002, pp. 973–993; b) P. Siemsen, R. C.
Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39,
2632–2657.
[2] For recent reviews on Sonogashira-type reactions, see: a) R. R.
Tykwinski, Angew. Chem. Int. Ed. 2003, 42, 1566–1568; b) E.
Negishi, L. Anastasia, Chem. Rev. 2003, 103, 1979–2017; c) K.
Sonogashira, in: Handbook of Organopalladium Chemistry for
Organic Synthesis (Eds.: E. Negishi, A. de Meijere), Wiley-In-
terscience, New York, 2002, pp. 493–529; d) K. Sonogashira, J.
Organomet. Chem. 2002, 653, 46–49; e) K. Sonogashira, in:
Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH, Weinheim, 1998, pp. 203–209; f) R.
Rossi, A. Carpita, F. Bellina, Org. Prep. Proced. Int. 1995, 27,
127–160.
[3] a) Acetylene Chemistry (Eds.: F. Diederich, P. J. Stang, R. R.
Tykwinski), Wiley-VCH, Weinheim, 2005; b) U. H. F. Bunz,
Chem. Rev. 2000, 100, 1605–1644; c) J. M. Tour, Acc. Chem.
Res. 2000, 33, 791–804; d) R. E. Martin, F. Diederich, Angew.
Chem. Int. Ed. 1999, 38, 1350–1377; e) J. M. Tour, Chem. Rev.
1996, 96, 537–553; f) Modern Acetylene Chemistry (Eds.: P. J.
Stang, F. Diederich), Wiley-VCH, Weinheim, 1995.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
N. A. Bumagin, L. I. Sukhomlinova, E. V. Luzikova, T. P. Tots-
taya, I. P. Beletskaya, Tetrahedron Lett. 1996, 37, 897–900.
S. Bhattachrya, S. Sengupta, Tetrahedron Lett. 2004, 45, 8733–
8736.
C. Wolf, R. Lerebours, Org. Biomol. Chem. 2004, 2, 2161–2164.
4080
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4073–4081

A (Dipyridin-2-ylmethyl)amine-Derived Palladium() Chloride Complex
FULL PAPER
[22] a) N. E. Leadbeater, M. Marco, B. J. Tominack, Org. Lett.
2003, 5, 3919–3922; b) P. Appukkuttan, W. Dehaen, E.
Van der Eycken, Eur. J. Org. Chem. 2003, 4713–4716.
[23] C. Nájera, J. Gil-Moltó, S. Karlström, L. R. Falvello, Org. Lett.
2003, 5, 1451–1454.
[24] Copper-free cross-coupling reactions between terminal alkynes
and iodoarenes in water with use of PdCl2 (1 mol-%) as catalyst
and pyrrolidine (5 equiv.) as base (25 to 50 °C for 1 d) have
recently been described: B. Liang, M. Dai, J. Chen, Z. Yang,
J. Org. Chem. 2005, 70, 391–393.
[25] For the preparation of complex 1, see: C. Nájera, J. Gil-Moltó,
S. Karlström, Adv. Synth. Catal. 2004, 346, 1798–1811.
[26] For representative work focused on palladium-catalysed coup-
lings between alkynes and enynes, see: a) B. M. Trost, M. T.
Sorum, C. Chan, A. E. Harms, G. Rühter, J. Am. Chem. Soc.
1997, 119, 698–708; b) U. Lücking, A. Pfaltz, Synlett 2000,
1261–1264; c) L. Chen, C.-J. Li, Tetrahedron Lett. 2004, 45,
2771–2774.
[27] For palladium-catalysed dimerization of terminal alkynes to
enynes, see: a) M. Rubina, V. Gevorgyan, J. Am. Chem. Soc.
2001, 123, 11107–11108; b) C. Yang, S. P. Nolan, J. Org. Chem.
2002, 67, 591–593.
2004, 1559–1563; c) M. Moreno Mañas, R. Pleixats, Acc.
Chem. Res. 2003, 36, 638–643.
[29] Y. Uozumi, R. Nakao, Angew. Chem. Int. Ed. 2003, 42, 194–
197.
[30] The role of oxygen as cooxidant in the homocoupling of al-
kynes in CH3CN/Et3N in the presence of (PPh3)2PdCl2 (3 mol-
%), CuI (3 mol-%) and Ph3P as catalysts has recently been de-
scribed [ref.[4b]].
[31] E. O. Chukhadzhyan, L. A. Manasyan, A. T. Babayan, Khi-
miya Geterotsiklicheskikh Soedinenii 1988, 11, 1481–1483;
Chem. Abstr. 1988, 111, 57472.
[32] Y. Ma, C. Song, W. Jiang, Q. Wu, Y. Wang, X. Liu, M. B.
Andrus, Org. Lett. 2003, 5, 3317–3319.
[33] C. Conn, R. Simón, F. Coraro, T.-L. Hargraves, P. Ibrahim,
Bioorg. Chem. Lett. 2001, 11, 2565–2568.
[34] N. Miyaura, K. Yamada, H. Suginome, A. Suzuki, J. Am.
Chem. Soc. 1985, 107, 972–980.
[35] a) G. Zweifel, R. A. Lynd, R. E. Murray, Synthesis 1977, 52–
53; b) H. Suzuki, M. Aihara, H. Yamamoto, Y. Takamoto, T.
Ogawa, Synthesis 1988, 236–238.
Received: May 5, 2005
Published Online: August 8, 2005
[28] a) M. T. Reetz, E. Westermann, Angew. Chem. Int. Ed. 2000,
39, 165–168; b) M. T. Reetz, J. G. de Vries, Chem. Commun.
Eur. J. Org. Chem. 2005, 4073–4081
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4081