Direct coupling reactions of alkynylsilanes catalyzed by palladium(II) chloride and a di(2-pyridyl)methylamine-derived palladium(II) chloride complex in water and in NMP

Article abstract of DOI:10.1002/adsc.200606033

Symmetrical internal alkynes can be prepared either by diarylation of mono- and bis(trimethylsilyl)acetylene (TMSA and BTMSA) catalyzed by ligand-less palladium(II) chloride or by a di(2-pyridyl) methylamine-derived palladium(II) chloride complex 1 (typic

Full text of DOI:10.1002/adsc.200606033

FULL PAPERS
DOI: 10.1002/adsc.200606033
Direct Coupling Reactions of Alkynylsilanes Catalyzed by
Palladium(II) Chloride and a Di(2-pyridyl)methylamine-Derived
Palladium(II) Chloride Complex in Water and in NMP
Juan Gil-Moltóa and Carmen Nájeraa,*
a
Departamento de Química Orgánica , Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de
Alicante, Apartado 99, 03080 Alicante, Spain
Fax: (+34)-965-903-549; e-mail: cnajera@ua.es
Received: January 31, 2006; Accepted: July 6, 2006
Abstract: Symmetrical internal alkynes can be pre- can be coupled with TMSA, BTMSA and silylated
pared either by diarylation of mono- and bis(trime- terminal alkynes under heating or at room tempera-
thylsilyl)acetylene (TMSA and BTMSA) catalyzed ture, whereas for aryl bromides couplings are per-
by ligand-less palladium(II) chloride or by a di(2-pyr- formed under water reflux or at 1108C in the case of
idyl)methylamine-derived palladium(II) chloride NMP. Complex 1 can be reused during several cycles
complex 1 (typical 0.1–1 mol% of Pd loading) in either in water or in NMP without loss of catalytic
water using pyrrolidine as base and tetra-n-butylam- activity. These simple reaction conditions allow the
monium bromide as additive. Alternatively, this preparation of internal alkynes without secondary
same process is performed in NMP in the presence products, most probably by succesive protiodesilyla-
of tetra-n-butylammonium acetate (TBAA) as base tion-Sonogashira coupling.
with even lower Pd loadings (0.001–1 mol% Pd).
The same reaction conditions are applied to the syn-
thesis of unsymmetrical internal alkynes by monoar- Keywords: alkynylation; aryl halides; diarylalkynes;
ylation of silylated terminal alkynes. Aryl iodides dipyridyl ligands; palladium; trimethylsilylacetylenes
Introduction
et al. for the straightforward one-pot synthesis of un-
symmetrical alkynes.[6] Oxime-derived palladacycles
Symmetrical and unsymmetrical internal alkynes play have been used as catalysts in our group to promote
an important role as building blocks in many synthetic the diarylation of TMSA and BTMSA in the presence
transformations and are common units of natural of CuI or tetra-n-butylammonium bromide (TBAB)
products and new materials such as conjugated as co-catalysts.[7] Copper-free sila-Sonogashira diaryla-
oligomers and polymers, liquid crystals, non-linear tion of TMSA with aryl iodides in the presence of
materials, molecular wires, and other engineering ma- MeONa in methanol has been performed with Pd-
terials.[1] The most important strategies for the synthe-
sis of diarylalkynes are based on palladium-catalyzed
ACHTREUNG
cross-coupling reactions.[2] In the case of symmetrical protected terminal alkynes instead of unprotected
alkynes the diarylation of acetylene with aryl iodides acetylenes (Sonogashira versus sila-Sonogashira reac-
under typical Sonogashira conditions (with CuI as co- tion) is to suppress the formation of by-products from
catalyst) was described.[3] In order to avoid the use of alkynes, such as diynes and enynes. In addition, the
toxic acetylene, which is also difficult to handle in deprotection step can be avoided, thus making the in-
exact amounts, mono- and bis(trimethylsilyl)acetylene troduction of an alkyne during a synthetic process
(TMSA and BTMSA) are used as acetylene equiva- more simple. There are some protocols for the synthe-
lents in the so-called sila-Sonogashira reaction.[4] In sis of unsymmetrical alkynes from silylated terminal
this type of sila-Sonogashira reaction a transmetala- acetylenes with aryl iodides and triflates under
tion from silicon to copper has been proposed when copper-free conditions by using other promotes, such
using CuCl as co-catalyst.[5] A sequential Sonogashira as fluorides,[9] and or silver salts.[10] Yang and Nolan
reaction with TMSA followed by addition of 40 have described an efficient coupling of aryl bromides
mol% of water and 1,8-diazabicyclo
ene (DBU) has been recently described by Grieco carbenes from Pd
ACHTREUNG
AHCTREUNG
1874
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1874 – 1882

Direct Coupling Reactions of Alkynylsilanes
FULL PAPERS
um salt in N,N-dimethylacetamide (DMAc) at Results and Discussion
808C.[11] The same type of coupling has been carried
out under microwave heating using Pd
mol%) and tri(o-tolyl)phosphine as catalyst in the Water
A
ACHTREUNG
presence of tetra-n-butylammonium chloride (TBAC)
in DMF at 1008C.[12] However, this type of direct cou- Symmetrically substituted diarylacetylenes were pre-
pling with alkynylsilanes has not been performed in pared in a single step by using TMSA and BTMSA as
neat water.
synthetic equivalents of acetylene. For the implemen-
We have recently described that PdCl2 and the tation of this diarylation process in water as solvent,
di(2-pyridyl)methylamine-based palladium(II) chlo- the same reaction conditions established for the aryla-
ride complexes 1[13] and 2[14] (Figure 1) showed high tion of terminal alkynes,[13c] pyrrolidine as base and
TBAB as additive, were used. Either TMSA or
BTMSA were coupled with representative activated
and deactivated aryl iodides and bromides under
water reflux by using 1 mol% of di(2-pyridyl)methyl-
amine-derived complex
1 or PdCl2 as catalysts
(Scheme 1 and Table 1). Initial studies for the cou-
pling of 4-chloroiodobenzene and TMSA needed
2.5 equivs. of pyrrolidine and 6 h for full conversion
(Table 1, entries 1–3), whereas in the case of BTMSA
the diarylation took place faster (2 h) with only
1.5 equivs. of pyrrolidine (Table 1, entries 4 and 5) to
Figure 1. Di(2-pyridyl)methylamine-derived palladium di-
chloride catalysts.
catalytic activity in Heck, Suzuki, and Sonogashira re-
actions in water[13,14] and in NMP.[13] In this contribu-
tion we report that the palladium complex 1 and also
ligand-less PdCl2 can be efficient catalysts in the
direct coupling reaction of alkynylsilanes either in
water or in NMP for the synthesis of symmetrical and
unsymmetrical diarylalkynes.
Scheme 1. Diarylation of TMSA and BTMSA.
Table 1. Diarylation of TMSA and BTMSA in H2O.[a]
Entry
X
Y
R
Cat [mol% Pd]
Pyrrolidine [equivs.]
T [8C]
Time
No.
Yield [%][b]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OMe
OMe
OMe
OMe
Cl
Cl
OMe
OMe
H
H
H
TMS
TMS
TMS
TMS
H
1 (1)
1 (1)
PdCl2 (1)
1 (1)
PdCl2 (1)
1 (4)
PdCl2 (4)
1 (1)
PdCl2 (1)
1 (1)
PdCl2 (1)
1 (1)
PdCl2 (1)
1 (1)
1.5
2.5
2.5
1.5
1.5
1.5
1.5
2.5
2.5
1.5
1.5
1.5
1.5
1.5
1.5
100
100
100
100
100
25
23 h
6 h
6 h
2 h
2 h
5 d
5 d
5 h
8.5 h
6 h
3.5 h
8.5
7 h
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3bb
3bb
3bb
3bb
3aa
3aa
3bb
3bb
81
100 (94)
100
83 (76)
86
74
94 (89)
100 (90)
100
100
100
25
100
100
100
100
100
100
100
100
9
H
10
11
12
13
14
15
TMS
TMS
TMS
TMS
TMS
TMS
80
100[c]
100[c]
100[c]
8 h
8 h
PdCl2 (1)
[a]
Reaction conditions: aryl halide (1 mmol), TMSA or BTMSA (1.2 mmol), pyrrolidine, TBAB (0.5 mmol), Pd catalyst (see
column), H2O (2 mL), 100 or 258C.
Yield determined by GC based on aryl halide using decane as internal standard. In brackets, isolated yield of compound
3 after flash chromatography.
[b]
[c]
A 3/1 mixture of compound 3 and silylated alkyne was obtained.
Adv. Synth. Catal. 2006, 348, 1874 – 1882
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1875

Juan Gil-Moltó and Carmen Nájera
FULL PAPERS
give internal alkyne 3aa in good yields. Alternatively, alyst. It can be concluded that BTMSA is a better
the last process could be carried out at room tempera- acetylene equivalent than TMSA for the diarylation
ture in 5 d by increasing to 4 mol% the loading of Pd reaction in water.
(Table 1, entries 6 and 7). When the couplings be-
For the synthesis of unsymmetrical internal alkynes
tween 4-chloroiodobenzene and BTMSA (Table 1, en- in water, different silylated terminal alkynes were ary-
tries 4 and 5) were carried out under microwave irra- lated under the above-mentioned reaction conditions
diation at 1108C (80 W)[15] with both catalysts irrepro- (Scheme 2 and Table 2). The arylation of 1-phenyl-2-
ducible mixtures of diarylated product 3aa and mono- (trimethylsilyl)acetylene with 4-chloroiodobenzene in
arylated silylated compound were obtained. The use
of polymer-supported complex 2 (1 mol% Pd) as cat-
alyst for the reaction between 4-chloroiodobenzene
with TMSA and BTMSA (under the same reaction
conditions as indicated in Table 1, entries 2 and 4)
gave quantitative yields of compound 3aa in 9 and
7 h, respectively.
Scheme 2. Arylation of silylated terminal alkynes in H2O.
Diarylation of TMSA and BTMSA with deactivat-
ed 4-methoxyiodobenzene could be performed under refluxing water catalyzed by complex 1 or PdCl2
similar reaction conditions to activated 4-chloroiodo- could be accomplished with 1 to 0.01 mol% of Pd
benzene to provide symmetrical alkyne 3bb (Table 1, achieving 2300 or 1450 turnover number per hour
entries 8–11). The experiments were followed by GC (TOF), respectively, to afford the internal alkyne 3ac
showing that the mono- and diarylation were compet- (Table 2, entries 1–5). Alternatively, the reaction
itive processes. 4-Chloro- and 4-methoxybromoben- could be performed at room temperature in 1 day
zene reacted with BTMSA to give mixtures of 3aa with 1 mol% loading of catalyst (Table 2, entries 6
and 3bb, respectively but also monoarylated silylated and 7). A quantitative yield was also obtained after
alkynes in a ca. 3/1 ratio (Table 1, entries 12–15). On 1 h by using the polymer-supported complex 2 (0.1
the other hand, 4-chlorobromobenzene gave exclu- mol% Pd) as catalyst under the reaction conditions
sively compound 3aa when complex 1 was used as cat- indicated in Table 2, entry 3. When this reaction was
Table 2. Arylation of silylated terminal alkynes in H2O.[a]
Entry
ArX
R
Cat [mol% Pd]
T [8C]
Time
No.
Yield [%][b]
1
2
3
4
5
6
7
8
4-ClC6H4I
Ph
1 (1)
PdCl2 (1)
1 (0.1)
1 (0.01)
PdCl2 (0.01)
1 (1)
PdCl2 (1)
1 (0.5)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (1)
PdCl2 (1)
1 (0.1)
PdCl2 (0.1)
1 (1)
PdCl2 (1)
1 (1)
PdCl2 (1)
100
100
100
100
100
25
1 h
1 h
1 h
4 h
6 h
1 d
3ac
3ac
3ac
3ac
3ac
3ac
3ac
3ac
3ad
3ad
3ae
3ae
3af
3af
3af
3af
3bc
3bc
3ac
3ac
3bc
3bc
100 (92)
95
95
92
87
96
92
85
100 (93)
100
99 (89)
88
21
19
92
6
97 (85)
94
79
25
1 d
110
100
100
100
100
100
100
25
30 min[c]
4 h
9
3-Pyridyl
2-Thienyl
n-C3H7
10
11
12
13
14
15
16
17
18
19
20
21
22
4 h
1.5 h
1.5 h
5.5 h
5.5 h
1 d
1 d
2 h
3 h
3 h
25
4-MeOC6H4I
4-ClC6H4Br
Ph
Ph
Ph
100
100
100
100
100
100
2 h
8 h
8 h
66
90
71
4-MeOC6H4Br
[a]
Reaction conditions: aryl halide (1 mmol), silylated alkyne (1.2 mmol), pyrrolidine (1.5 mmol), TBAB (0.5 mmol), Pd cat-
alyst (see column), H2O (2 mL), 100 or 258C.
Yield determined by GC based on aryl halide using decane as internal standard. In brackets, isolated yield of compound
3 after flash chromatography.
[b]
[c]
The reaction was performed under microwave irradiation conditions (80 W).
1876
www.asc.wiley-vch.de
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1874 – 1882

Direct Coupling Reactions of Alkynylsilanes
FULL PAPERS
performed under microwave irradiation at 1108C (80
W)[15] with complex 1 (0.5 mol%), product 3ac was
obtained in 85% yield after 30 min (Table 2, entry 8).
Other silylated terminal alkynes, such as 3-pyridyl-
and 2-thienylacetylene were arylated in similar way
with 4-chloroiodobenzene to provide compounds 3ad
and 3ae in good yields (Table 2, entries 9–12). Howev-
er, 1-(trimethylsilyl)pent-1-yne gave poor conversions
in refluxing water, probably due to protiodesilylation
and evaporation of the in situ formed pent-1-yne (see
below). This problem could be avoided by performing
the reaction at room temperature during 1 day with
Scheme 4. Desilylation of 1-phenyl-2-(trimethylsilyl)acety-
lene in H2O.
complex 1 as catalyst, affording a 92% yield of 1-(4- petitive process through a transmetalation reaction
chlorophenyl)pent-1-yne (3af), whereas PdCl2 gave from silicon to copper cannot be ruled out.
only 6% yield (Table 2, entries 13–16). In the case of
The direct coupling of alkynylsilanes can be per-
the arylation of 1-phenyl-2-(trimethylsilyl)acetylene formed under water reflux or at room temperature
with deactivated 4-methoxyiodobenzene, product 3bc either by using complex 1 or ligand-less PdCl2 as cata-
was obtained in good yield with both catalysts lysts and pyrrolidine as base in the presence of TBAB
(Table 2, entries 17 and 18). For the couplings be- as additive by using aryl iodides or bromides in good
tween 1-phenyl-2-(trimethylsilyl)acetylene and 4- yields. This methodology allows the synthesis of sym-
chloro- or 4-methoxybromobenzene the loading of Pd metrical and unsymmetrical internal alkynes.
was increased to 1 mol% to get compounds 3ac and
3bc, respectively, in good yields, complex 1 being a su-
perior catalyst than PdCl2 (Table 2, entries 19–22).
Di- and Monoarylation of Silylated Acetylenes in
The catalytic activity of complex 1 (1 mol%) was NMP
maintained during 4 cycles by succesive addition of
the reagents to the reaction, according to the condi- Initial studies on the diarylation of TMSA and
tions of entry 1 in Table 2 (Scheme 3). After 1 h reac- BTMSA were performed with 4-chloroiodobenzene
tion time each cycle occurred in higher than 95% and complex 1 or PdCl2 as catalysts using TBAA as
yield, with no deactivation of complex 1.
base in NMP (Scheme 5 and Table 3). These reaction
In order to get a further insight into the reaction
mechanism, 1-phenyl-2-(trimethylsilyl)acetylene was
treated with 1.5 equivs. of pyrrolidine under water
reflux, and the desilylation process took place in 16 h
(Scheme 4). However, in the presence of complex 1
(1 mol%) quantitative formation of phenylacetylene
was observed after 3.5 h in refluxing water. This ob-
servation indicates that the process takes place mainly
through a protiodesilylation reaction followed by So-
nogashira-type coupling. In order to rule out the
transmetalation from silicon to copper, ICP-MS anal-
Scheme 5. Diarylation of TMSA and BTMSA in NMP.
yses of both reaction media were performed. Traces conditions were found to be the most appropriate for
of copper were found in he Pd desilylation reaction. the Sonogashira couplings.[7,13c] The diarylation of
In the case of catalyst 1 2.903×10À5 mg of copper per TMSA was performed with 0.1 mol% of Pd at differ-
mg of complex were found and 2.397×10À4 mg of ent temperatures, such as 110, 60 and 408C. Full con-
copper in the case of PdCl2. For that reason, a com- version was obtained only at 1108C with both cata-
Scheme 3. Efficiency of catalyst 1 in the arylation of 1-phenyl-2-(trimethylsilyl)acetylene in H2O.
Adv. Synth. Catal. 2006, 348, 1874 – 1882
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1877

Juan Gil-Moltó and Carmen Nájera
FULL PAPERS
Table 3. Diarylation of TMSA and BTMSA with 4-chloroiodobenzene in NMP.[a]
Entry
R
Cat [mol% Pd]
T [8C]
Time
Yield [%][b]
TON
TOF [hÀ1]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
1 (0.1)
PdCl2 (0.1)
1 (0.1)
1 (0.1)
1 (1)
PdCl2 (1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
1 (0.1)
1 (4)
110
110
60
40
25
0.5 h
0.5 h
8 h
8.5 h
45 h
17 h
1.5 h
1.5 h
8 h
8.5 h
48 h
8 h
23 h
33 h
100 (89)
100
60
13
93
100 (90)
100
100
58
20
100 (88)
100
72
5
103
103
600
130
93
100
103
103
580
200
25
2×103
2×103
75
15
2
25
6
110
110
60
40
25
25
110
110
666
666
73
24
0.5
3
9
10
11
12
13
14
PdCl2 (4)
1 (0.01)
PdCl2 (0.01)
25
7200
500
313
15
[a]
Reaction conditions: aryl halide (1 mmol), TMSA or BTMSA (1.2 mmol), TBAA (1.5 mmol), Pd catalyst (see column),
NMP (2 mL).
[b]
Yield determined by GC based on aryl halide using decane as internal standard. In parenthesis, isolated yield of com-
pound 3aa after flash chromatography.
lysts in 30 min with TOF up to 2000 hÀ1 (Table 3, en- couplings TMSA gave also better results than
tries 1–4). For room temperature reactions using com- BTMSA.
plex 1 and PdCl2 as catalysts, the loading of Pd was
The stability of catalyst 1 in this diarylation reac-
increased to 1 mol% to get high yields in 45 and 17 h, tion was studied for the coupling between 4-chloroio-
respectively (Table 3, entries 5 and 6). When these ex- dobenzene and TMSA in NMP at 1108C with 0.1
periments were performed with BTMSA, similar re- mol% of Pd (Scheme 7). The efficiency of complex 1
sults were obtained although in lower TOFs than with was maintained during five consecutive cycles of
TMSA (Table 3, entries 7–12). The loading of Pd was 30 min to give product 3aa in quantitative yield.
decreased to 0.01 mol%, complex 1 was the only
Reaction conditions studies for the arylation of sily-
active species under these reaction conditions to pro- lated terminal alkynes were performed with silylated
vide compound 3aa in 72% yield (TOF=313 hÀ1) phenylacetylene and 4-chloroiodobenzene with com-
(Table 3, entries 13 and 14).
plex 1 and PdCl2 as catalysts (Scheme 8 and Table 5).
Diarylation of TMSA and BTMSA was performed The reaction could be carried out in good yields by
with different aryl iodides and bromides in NMP with using 0.1 mol% of complex 1 at 40, 60 or 1108C
complex 1 and PdCl2 as catalysts and TBAA as base (Table 5, entries 1–3). At 1108C both catalysts (0.1
(Scheme 6 and Table 4). The diarylation with 4-chloro- mol%) gave full conversion after 15 min with a TOF
iodobenzene, 4-methoxyiodobenzene, and 1-iodo- of 4000 hÀ1 (Table 5, entries 3 and 4). At this tempera-
naphthalene took place more efficiently in the case of ture, the loading of Pd could be decreased to 0.001
TMSA than BTMSA (Table 4, entries 1–14). Both mol% while still getting good yields of product 3ac in
catalysts showed similar efficiency at 1108C, but at 1 d with a TOF up to 37,500 hÀ1 (Table 5, entries 5
room temperature PdCl2 was more efficient than com- and 6). For the couplings at room temperature in-
plex 1. When the related aryl bromides were allowed creasing the loading of Pd to 1 mol% was necessary
to react with TMSA and BTMSA in NMP at 1108C, a in order to perform the reaction in 1 d (Table 5, en-
similar loading of Pd (0.1 mol%) was used to that for tries 7–9).
iodides, but longer reaction times were needed for
The syntheses of unsymmetrical internal alkynes 3
good conversions (Table 4, entries 15–22). In these in NMP were performed with representative activated
and deactivated aryl iodides and bromides with differ-
ent silylated terminal alkynes at 1108C and with a
loading of 0.1 mol% of catalysts (Scheme 9 and
Table 6). In the case of 4-chloroiodobenzene, the ary-
lation of different silylated alkynes such as phenylace-
tylene, 3-pyridylacetylene, 2-thienylacetylene, and
pent-1-yne afforded very good yields in short reaction
times (15 min to 3.5 h) (Table 6, entries 1–8). Similar
behaviour was observed in the couplings of 4-meth-
Scheme 6. Synthesis of symmetrical alkynes by diarylation
of TMSA and BTMSA in NMP.
1878
www.asc.wiley-vch.de
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1874 – 1882

Direct Coupling Reactions of Alkynylsilanes
FULL PAPERS
Table 4. Diarylation of TMSA and BTMSA in NMP.[a]
Entry
ArX
R
Cat [mol% Pd]
T [8C]
Time
No.
Yield [%][b]
1
2
3
4
5
6
7
8
4-ClC6H4I
H
H
H
H
TMS
TMS
TMS
TMS
H
1 (0.1)
PdCl2 (0.1)
1 (1)
PdCl2 (1)
1 (0.1)
PdCl2 (1)
1 (4)
PdCl2 (4)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
1 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
1 (0.1)
110
110
25
0.5 h
0.6 h
45 h
17 h
1.5 h
1.5 h
48 h
8 h
2 h
2 h
4 h
4 h
3.5 h
1 h
10 h
7 h
5 h
4 h
48 h
48 h
4 h
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3bb
3bb
3bb
3bb
3cc
3cc
3aa
3aa
3aa
3aa
3bb
3bb
3cc
3cc
100 (89)
100
93
100 (90)
100
100
100 (88)
100
90 (79)
100
100
100
98 (79)
92
96
96
77
60
67 (53)
20
97
89
25
110
110
25
25
9
4-MeOC6H4I
110
110
110
110
110
110
110
110
110
110
110
110
110
110
10
11
12
13
14
15
16
17
18
19
20
21
22
H
TMS
TMS
H
TMS
H
1-Iodonaphthalene
4-ClC6H4Br
H
TMS
TMS
H
TMS
H
4-MeOC6H4
1-Bromonaphthalene
1 (0.1)
1 (0.1)
TMS
4 h
[a]
Reaction conditions: aryl halide (1 mmol), TMSA or BTMSA (1.2 mmol), TBAA (1.5 mmol), Pd catalyst (see column),
NMP (2 mL), 110 or 258C.
Yield determined by GC based on aryl halide using decane as internal standard. In parenthesis, isolated yield of com-
pound 3 after flash chromatography.
[b]
Scheme 7. Efficiency of catalyst 1 in the diarylation reaction of TMSA in NMP.
tries 12–15). However, the coupling between 4-me-
thoxybromobenzene and 1-phenyl-2-(trimethylsilyl)-
acetylene proceeded in a modest 28% yield (Table 6,
entry 16).
The catalytic activity of complex 1 was evaluated
by performing the arylation of 1-phenyl-2-(trimethyl-
silyl)acetylene with 4-chloroiodobenzene in NMP at
1108C (Scheme 10). The same efficiency was observed
after addition of the reagents to the reaction during 5
consecutive cycles of 15 min.
Scheme 8. Arylation of 1-phenyl-2-(trimethylsilyl)acetylene
in NMP.
oxyiodobenzene with silylated phenyl-, 3-pyridyl-, and
The mechanism of the coupling reaction of alkynyl-
2-thienylacetylenes (Table 6, entries 9–11). With re- silanes in NMP was studied by treatment of 1-phenyl-
spect to 4-chlorobromobenzene, the reaction with si- 2-(trimethylsilyl)acetylene with TBAA at 1108C in
lylated phenylacetylene and pent-1-yne took place the absence and in the presence of complex 1
under 0.1 mol% loading of both catalysts in good (Scheme 11). Under both reaction conditions the pro-
yields and 45 min to 6.5 h reaction times (Table 6, en- tiodesilylation took place in 15 min, much faster than
Adv. Synth. Catal. 2006, 348, 1874 – 1882
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1879

Juan Gil-Moltó and Carmen Nájera
Table 5. Arylation of 1-phenyl-2-(trimethylsilyl)acetylene with 4-chloroiodobenzene in NMP.[a]
FULL PAPERS
Entry
Cat [mol% Pd]
T [8C]
Time
Yield [%][b]
TON
TOF [hÀ1]
1
2
3
4
5
6
7
8
9
1 (0.1)
1 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.001)
PdCl2 (0.001)
1 (0.1)
1 (1)
PdCl2 (1)
40
60
5.5 h
0.5 h
15 min
15 min
24 h
24 h
13 d
88
84
100 (94)
100
90
87
96
91
88
880
840
160
1680
4000
4000
37,500
36,250
3
110
110
110
110
25
1000
1000
9×105
8.7×105
960
25
25
23 h
23 h
91
88
4
4
[a]
Reaction conditions: aryl halide (1 mmol), 1-phenyl-2-(trimethylsilyl)acetylene (1.2 mmol), TBAA (1.5 mmol), Pd catalyst
(see column), NMP (2 mL).
Yield determined by GC based on aryl halide using decane as internal standard. In parenthesis, isolated yield of com-
pound 3ac after flash chromatography.
[b]
Table 6. Synthesis of unsymmetrical internal alkynes in NMP.[a]
Entry
ArX
R
Cat [mol% Pd]
Time
No.
Yield [%][b]
1
2
3
4
5
6
7
8
4-ClC6H4I
Ph
Ph
3-Pyridyl
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
1 (0.1)
1 (0.1)
1 (0.1)
15 min
15 min
3.5 h
2.5 h
2 h
3.5 h
0.5 h
1 h
3ac
3ac
3ad
3ad
3ae
3ae
3af
3af
3bc
3bd
3be
3ac
3ac
3af
3af
3bc
100 (94)
100
87 (85)
97
100 (89)
97
100 (84)
97
98 (91)
74 (62)
80
72 (63)
37
2-Thienyl
n-C3H7
9
4-MeOC6H4I
4-ClC6H4Br
Ph
15 min
3.5 h
2.5 h
45 min
3 h
10
11
12
13
14
15
16
3-Pyridyl
2-Thienyl
Ph
PdCl2 (0.1)
1 (0.1)
PdCl2 (0.1)
1 (0.1)
n-C3H7
6.5 h[c]
3 h[c]
7.5 h
31
87
28
4-MeOC6H4Br
Ph
[a]
Reaction conditions: aryl halide (1 mmol), silylated acetylene (1.2 mmol), TBAA (1.5 mmol), Pd catalyst (see column),
NMP (2 mL) at 1108C.
Yield determined by GC based on aryl halide using decane as internal standard. In parenthesis, isolated yield of com-
pound 3 after flash chromatography.
The reaction was performed in a pressure tube.
[b]
[c]
under water reflux (Scheme 4). It seems that the ace-
tate anion in NMP is a stronger base than the hydrox-
ide generated in water by the presence of pyrrolidine
for the desilylation process. This fast desilylation reac-
tion means that the reaction takes place mainly by ar-
Scheme 9. Arylation of silylated terminal alkynes in NMP.
Scheme 10. Efficiency of catalyst 1 in the arylation reaction of 1-phenyl-2-(trimethylsilyl)acetylene in NMP.
1880
www.asc.wiley-vch.de
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1874 – 1882

Direct Coupling Reactions of Alkynylsilanes
FULL PAPERS
Experimental Section
General Remarks
The reagents and solvents were obtained from commercial
sources and were generally used without further purifica-
tion. Flash chromatography was performed on silica gel 60
(0.040–0.063 mm, Merck). Thin layer chromatography was
perfomed on Polygram® SIL G/UV254 plates. Melting points
were determined on a Reicher Thermovar apparatus. Gas
chromatographic analyses were performed on a HP-6890 in-
strument equipped with a WCOT HP-1 fused silica capillary
column. IR data were collected on a Nicolet Impact-400D-
Scheme 11. Desilylation of 1-phenyl-2-(trimethylsilyl)acety-
lene in NMP.
1
FT spectrophometer in cmÀ1. H NMR spectra were record-
ed on Bruker AC-300 (300 MHz) and when specified on a
Bruker Advance-DRX-500 (500 MHz) spectrometer. Chem-
ical shifts are reported in ppm using tetramethylsilane
(TMS, d=0.00) as internal standards. 13C NMR spectra were
recorded at 75 MHz with CDCl3 as the internal reference.
ylation of the in situ generated deprotected terminal
alkyne. Although, a competitive transmetalation from
silicon to traces of copper (see above) cannot be
ruled out.
EI-MS were measured on
a Mass Selective Detector
G2579 A from Agilent Technologies 5973N in m/z (rel. in-
tensity in % of base peak). ICP-MS analyses were per-
formed in a Thermo Elemental VG PQ-Excell spectometer.
The catalysts were weighed up in an electronic microscale
(Sartorius, XM1000P) with a precision of 1 mg. Microwave
reactions were performed with a CEM Discover Synthesis
Unit in glass vessels (10 mL) sealed with a septum under
magnetic stirring.
The direct coupling reaction with alkynylsilanes can
be performed in NMP either at 1108C or at room
temperature by using either complex 1 or ligand-less
PdCl2 as catalysts and TBAA as base using aryl io-
dides or bromides in good yields and with higher
TOFs than in water. This methodology allows the syn-
thesis of symmetrical and unsymmetrical internal al-
kynes.
Typical Procedure for the Palladium-Catalyzed Direct
Coupling of Alkynylsilanes in Water
Conclusions
A mixture of aryl halide (1 mmol), alkyne (1.2 mmol), tetra-
n-butylammonium bromide (161 mg, 0.5 mmol), pyrrolidine
(0.205 mL, 2.5 mmol, only for trimethysilylacetylene and
We can conclude that the di(2-pyridyl)methylamine-
derived complex 1 and PdCl2 are efficient pre-cata-
lysts for the direct di- and monoarylation of silylated 0.123 mL, 1.5 mmol, for the rest of the reactions), complex 1
or PdCl2 (see Tables) was stirred in water (2 mL) under
reflux or at room temperature and the reaction progress an-
alysed by GC. After the reaction was completed or stopped,
the mixture was extracted with EtOAc (3×15 mL). The or-
ganic phases were dried (MgSO4) and evaporated under
vacuum. The subsequent residue was purified by flash chro-
matography on silica gel.
alkynes either in water or in NMP as solvents using
pyrrolidine or TBAA as bases, respectively. The syn-
thesis of symmetrical and unsymmetrical internal al-
kynes can be carried out with activated and deactivat-
ed aryl iodides and bromides. Couplings with aryl io-
dides can be carried out under heating or at room
temperature. For the diarylation in neat water
BTMSA was the best acetylene equivalent, whereas
TMSA is the reagent of choice in NMP. In general, a
lower catalyst loading was necessary for the couplings
performed in NMP than in water and normal heating
gave better results than microwave irradiation. These
types of direct couplings with alkynylsilanes gave in-
Typical Procedure for the Palladium-Catalyzed Direct
Coupling of Alkynylsilanes in NMP
A solution of aryl halide (1 mmol), alkyne (1.2 mmol), tetra-
n-butylammonium acetate (452 mg, 1.5 mmol), complex 1 or
PdCl2 (see Tables) in NMP (2 mL) was heated at 1108C or
ternal alkynes with higher purity than the Sonogashira at the temperature indicated in the Tables. The conversion
reaction previously described by us.[13c] The very high
of the reaction was followed by GC. Subsequently the
cooled reaction was extracted with EtOAc (3×15 mL) and
water and the organic phase was dried (MgSO4) and evapo-
efficiency and stability of complex 1 was maintained
in both media, being suitable for reuse during several
rated under vacuum. The crude product was purified by
catalytic cycles. Under these very simple reaction con-
flash chromatography on silica gel.
ditions a protiodesilylation-Sonogashira type coupling
Compounds 3aa, 3bb, 3ac, 3ad, and 3bc are commercially
instead of transmetalation from silicon to traces of
copper seems to be the major reaction pathway.
available and compounds 3cc,[6] 3ae,[6] 3af,[7] and 3bd[16] have
been previously reported and were characterized by compar-
ison with their reported data. Physical, analytical and spec-
troscopic data of the newly synthesized compound is gevine
below.
Adv. Synth. Catal. 2006, 348, 1874 – 1882
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1881

Juan Gil-Moltó and Carmen Nájera
FULL PAPERS
1-(4-Methoxyphenyl)-2-thienylacetylene (3be): mp 558C;
Rf =0.15 (hexane); H NMR (CDCl3): d=7.44 (d, 2H, J=
[3] S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagi-
hara, Synthesis 1980, 627–630.
1
8.4 Hz), 7.25–7.24 (m, 2H), 6.99–6.98 (m, 1H), 6.83 (d, 2H,
J=8.4 Hz), 3.81 (s, 3H); 13C NMR (CDCl3): d 159.7, 132.9,
131.4, 127.0, 126.8, 123.6, 114.9, 114.0, 93.0, 81.2, 55.2; HR-
MS: m/z = 214.0453, calcd for C13H10OS: 214.0452.
[4] 2-Methylbut-3-yn-2-ol can also be used as acetylene
equivalent: A. Carpita, A. Lessi, R. Rossi, Synthesis
1984, 571–572.
[5] a) Y. Nishihara, K. Ikegashira, A. Mori, T. Hiyama,
Chem. Lett. 1997, 1233–1234; b) Y. Nishihara, K. Ike-
gashira, K. Hirabayashi, J. Ando, A. Mori, T. Hiyama,
J. Org. Chem. 2000, 65, 1780–1787.
[6] M. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa,
K. L. Hull, R. G. Brisbois, C. J. Markworth, P. A.
Grieco, Org. Lett. 2002, 4, 3199–3202.
Acknowledgements
We thank DGES of the Spanish Ministerio de Educación y
Ciencia
(MEC)
(grants:
BQU2001–0724-CO2–01,
[7] D. A. Alonso, C. Nájera, M. C. Pacheco, Adv. Synth.
CTQ2004–00808/BQU), the Generalitat Valenciana (grants:
GRUPOS05/11) and the University of Alicante for financial
support. J. G.-M. thanks the MEC for a predoctoral fellow-
ship.
Catal. 2003, 345, 1146–1158.
[8] M.-J. Wu, L.-M. Wei, C.-F. Lin, S.-P. Leou, L.-L. Wei,
Tetrahedron 2001, 57, 7839–7844.
[9] Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918–
920.
[10] a) Y. Koseki, K. Omino, S. Anzai, T. Nagasaka, Tetra-
hedron Lett. 2000, 41, 2377–2380; b) U. Halbes, P.
Bertus, P. Pale, Eur. J. Org. Chem. 2001, 4391–4393;
c) U. Halbes, P. Bertus, P. Pale, Tetrahedron Lett. 2001,
42, 8641–8644; d) U. Halbes, P. Bertus, P. Pale, Tetrahe-
dron Lett. 2002, 43, 2039–2042.
[11] C. Yang, S. P. Nolan, Organometallics 2002, 21, 1020–
1022.
[12] U. S. Sorensen, E. Pombo-Villar, Tetrahedron 2005, 61,
2697–2703.
[13] a) C. Nájera, J. Gil-Moltó, S. Karlström, L. R. Falvello,
Org. Lett. 2003, 5, 1451–1454; b) C. Nájera, J. Gil-
Moltó, S. Karlström, Adv. Synth. Catal. 2004, 346,
1798–1811; c) C. Nájera, J. Gil-Moltó, Eur. J. Org.
Chem. 2005, 4073–4081.
References
[1] a) Acetylene Chemistry: Chemistry, Biology, and Mate-
rial Science (Eds.: F. Diederich, P. J. Stang, R. R. Tyk-
winski), 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. Die-
derich, 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.
[2] For recent reviews on Sonogashira-type reactions, see:
a) J. A. Marsden, M. M. Haley, in: Metal-Catalyzed
Cross-Coupling Reactions, 2nd edn., (Eds.: A. de Mei-
jere, F. Diederich), Wiley-VCH, Weinheim, 2004,
pp. 317–394; b) R. R. Tykwinski, Angew. Chem. Int.
Ed. 2003, 42, 1566–1568; c) E. Negishi, L. Anastasia,
Chem. Rev. 2003, 103, 1979–2017; d) K. Sonogashira,
in: Handbook of Organopalladium Chemistry for Or-
ganic Synthesis, (Eds.: E.-I. Negishi, A. de Meijere),
Wiley, New York, 2002, pp. 493–529; e) K. Sonoga-
shira, J. Organomet. Chem. 2002, 653, 46–49; f) K. So-
nogashira, in: Metal-Catalyzed Cross-Coupling Reac-
tions, (Eds.: A. de Meijere, F. Diederich), Wiley-VCH,
Weinheim, 1998, pp. 203–209; g) R. Rossi, A. Carpita,
F. Bellina, Org. Prep. Proc. Int. 1995, 27, 127–160.
[14] C. Nájera, J. Gil-Moltó, S. Karlström, Tetrahedron
2005, 61, 12168–12176.
[15] Microwave reactions were performed with a CEM Dis-
cover Synthesis Unit (CEM Corp., Matthews, NC) with
a continuous focused microwave power delivery system
in glass vessels (10 mL) sealed with a septum under
magnetic stirring. The temperature of the reaction mix-
ture inside the vessel was monitored using a calibrated
infrared temperature control under the reaction vessel.
[16] Z. Novák, P. Nemes, A. Kotschy, Org. Lett. 2004, 6,
4917–4920.
1882
www.asc.wiley-vch.de
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1874 – 1882