Highly convenient, clean, fast, and reliable Sonogashira coupling reactions promoted by aminophosphine-based pincer complexes of palladium performed under additive-and amine-free reaction conditions

Article abstract of DOI:10.1002/adsc.200900112

Sequential addition of 1,1',1″-phosphine-triyltripiperidine and 1,3-diaminobenzene or resorci-nol to toluene solutions of (cyclooctadiene) palladium dichloride [Pd(cod)(Cl)₂] under nitrogen in "one pot" almost quantitatively yielded the aminophos-phine-based pincer complexes {[C₆H₃-2,6-(XP{piperi-dinyl}₂) ₂]Pd(Cl)} (X = NH 1; X = O 2). Complex 1 (and to a minor extent 2) proved to be efficient Sonogashira catalysts, which allow the quantitative coupling of various electronically deactivated and/or sterically hindered and functionalized aryl iodides and aryl bromides with several alkynes as coupling partners within very short reaction times and low catalyst loadings. Importantly, in contrast to most of the Sonogashira catalysts, which either are both air-and moisture-sensitive and/or require the addition of co-catalysts, such as copper(I) iodide [Cul], for ex- ample, or a large excess of an amine, the coupling reactions were carried out without the use of amines, co-catalysts or other aditives and without exclusion of air and moisture. Moreover, the desired products were exclusively formed (no side-products were detected) without employing an excess of one of the substrates. Ethylene glycol and potassium phosphate (K₃PO₄) were found to be the ideal solvent and base for this transformation. Experimental observations strongly indicate that palladium nanoparticles are not the catalytically active form of 1 and 2. On the other hand, their transformation into another homogeneous catalytically active species cannot be excluded.

Full text of DOI:10.1002/adsc.200900112

FULL PAPERS
DOI: 10.1002/adsc.200900112
Highly Convenient, Clean, Fast, and Reliable Sonogashira
Coupling Reactions Promoted by Aminophosphine-Based
Pincer Complexes of Palladium Performed under Additive-
and Amine-Free Reaction Conditions
Jeanne L. Bolligera and Christian M. Frecha,*
a
Department of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Fax : (+41)-44-635-6802; e-mail: chfrech@aci.uzh.ch
Received: February 18, 2009; Revised: March 16, 2009; Published online: April 6, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900112.
Abstract: Sequential addition of 1,1’,1’’-phosphine- ample, or a large excess of an amine, the coupling re-
triyltripiperidine and 1,3-diaminobenzene or resorci- actions were carried out without the use of amines,
nol to toluene solutions of (cyclooctadiene)palladium co-catalysts or other aditives and without exclusion
dichloride [PdACHTUNGTRENNUNG(cod)(Cl)2] under nitrogen in “one of air and moisture. Moreover, the desired products
pot” almost quantitatively yielded the aminophos- were exclusively formed (no side-products were de-
phine-based pincer complexes {[C6H3-2,6-(XP{piperi- tected) without employing an excess of one of the
dinyl}2)2]Pd(Cl)} (X=NH 1; X=O 2). Complex 1 substrates. Ethylene glycol and potassium phosphate
(and to a minor extent 2) proved to be efficient So- (K3PO4) were found to be the ideal solvent and base
nogashira catalysts, which allow the quantitative cou- for this transformation. Experimental observations
pling of various electronically deactivated and/or strongly indicate that palladium nanoparticles are
sterically hindered and functionalized aryl iodides not the catalytically active form of 1 and 2. On the
and aryl bromides with several alkynes as coupling other hand, their transformation into another homo-
partners within very short reaction times and low geneous catalytically active species cannot be exclud-
catalyst loadings. Importantly, in contrast to most of ed.
the Sonogashira catalysts, which either are both air-
and moisture-sensitive and/or require the addition of Keywords: C C coupling; cross-coupling; palladium;
co-catalysts, such as copper(I) iodide [CuI], for ex- pincer complexes
À
Introduction
of expensive starting materials. Moreover, most of
these catalysts are air- and moisture-sensitive, require
The Sonogashira reaction (cross-coupling of aryl or either a co-catalyst (CuI, ZnCl2 or FeCl3) and/or the
vinyl halides with terminal alkynes) belongs nowadays use of excess amines (sometimes even as solvents),
to an indispensable set of palladium-catalyzed cross- prolonged reaction times (typically 12–24 h with aryl
coupling reactions and is the most important method bromides), relatively high catalyst loadings (1–
for the synthesis of internal acetylenes,[1–3] which finds 5 mol%), and/or the use of an excess of one of the
its application in a wide range of organic processes, substrates for efficient and high-yielding product for-
such as the preparation of natural products,[5,6] phar- mations.[12–17] Among other reasons, PdCl
CHTUNTGRNE(NUNG PPh3)2,
2A
maceuticals,[7] biologically active molecules,[8] liquid PdCl2/PPh3, and Pd
AHCTUNGETRG(NNNU PPh3)4 therefore still are the most
crystalline materials and conducting polymers,[9] or widely used catalysts in organic chemistry even
molecular electronics in general.[10] Although recent though high catalyst loadings (typically 5 mol%),
developments have led to a considerable increase in large amounts of copper(I) iodide [for the in situ gen-
the activity of Sonogashira catalysts, of which some eration of copper(I) acetylides],[18] and excess of an
efficiently couple sterically hindered substrates or oc- amine, such as diisopropylamine are required. Thus,
casionally even aryl chlorides,[11] their syntheses are the development of more efficient, but cheap and
often time-consuming, difficult, and/or require the use easily prepared catalysts, which allow the perfor-
Adv. Synth. Catal. 2009, 351, 891 – 902
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891

Jeanne L. Bolliger and Christian M. Frech
FULL PAPERS
mance of Sonogashira cross-coupling reactions with loadings (0.005 mol%) even for electronically deacti-
low catalyst loadings under additive- and amine-free vated and/or sterically hindered and functionalized
reaction conditions and without the need of exclusion substrates. Ethylene glycol and K3PO4 were found to
of air and moisture, is of high general interest.
be the ideal solvent and base for this transformation.
We report herein the catalytic activity of amino- Ethylene glycol was neither degassed nor dried prior
phosphine-based pincer complexes of palladium with to use,[23] since these catalysts allow one to carry out
the general formula of {[C6H3-2,6-(XP{piperidi- Sonogashira coupling reactions without excluding air
nyl}2)2]Pd(Cl)} (X=NH 1; X=O 2) in Sonogashira and moisture.[24] Furthermore, in contrast to most
known catalysts, no excess of neither substrate is re-
quired for the quantitative yield of the coupling prod-
ucts.[25] Indeed, homocoupled products or other side
reactions were not detected under these reaction con-
ditions, which makes the product separation very
easy. In sharp contrast, the inclusion of copper salts
or other co-catalysts, such as ZnCl2 and FeCl3 and/or
additives, for example, tetrabutylammonium bromide
was found to promote the formation of side-products.
Catalyst 1 was found to be generally more active
when compared with complex 2 (see Table 1). For ex-
ample, phenyl iodide and ethynylbenzene underwent
À
cross-coupling reactions, which fulfill most of the de- complete C C coupling into 1,1’-ethyne-1,2-diyldiben-
sired catalyst properties (Scheme 1).
zene in the presence of K3PO4 and only 0.005 mol%
of 1 within less than 15 min in ethylene glycol at
1408C, whereas a reaction time of 1 hour was necessa-
ry with catalyst 2 (Table 1, entries 1 and 3). Similarly,
when 1-ethynyl-2,4,5-trimethylbenzene was used as
À
coupling partner complete C C coupling was ob-
served within a 15 min reaction time with catalyst 1
(Table 1, entry 4). Exclusive formation of 1-methoxy-
4-(phenylethynyl)benzene and 4-(phenylethynyl)ani-
line, respectively, was observed with electronically de-
activated substrates such as 4-iodoanisole or 4-iodo-
Scheme 1. Sonogashira cross-coupling reactions of aryl hal-
ides with terminal acetylenes catalyzed by {C6H3-2,6-[XP(pi-
peridinyl)2]2Pd(Cl)} (X=NH 1; X=O 2).
AHCTUNGTREGaNNUN niline. Only 15 min were required for quantitative
product formation with 1 (Table 1, entries 5 and 7),
whereas 1 hour was required to achieve a yield of
Results and Discussion
92% of 4-(phenylethynyl)aniline with catalyst
(Table 1, entry 9). The same yields and conversion
2
The aminophosphine-based pincer complexes 1 and 2 rates were obtained with 1-ethynyl-2,4,5-trimethylben-
were recently shown to be extremely efficient Heck zene as coupling partner (Table 1, entries 6 and 10).
and Suzuki catalysts, which are prepared in excellent Excellent conversion rates and yields were also ob-
yields from very cheap starting materials in an ex- served when 4-iodophenol was used as coupling part-
tremely short and simple way {1 and 2 can be isolated ner (Table 1, entries 11 and 12). Full conversions were
as analytically pure and colorless solids from “one- obtained within only 15 min with 1. The same yields
pot” reactions of [Pd
ACHTUNGRTEN(NUNG cod)(Cl)2] (cod=cycloocta- and conversion rates were noticed when sterically hin-
diene), 1,1’,1’’-phosphinetriyltripiperidine and 1,3-di- dered 2-iodotoluene was coupled with ethynylbenzene
A
1-ethynyl-2,4,5-trimethylbenzene,
respectively
under N2 within less than one hour}.[21] Remarkably, (Table 1, entries 13 and 16). On the other hand, re-
the catalysts remain stable in solution for several tarded conversion was observed when 2-iodobiphenyl
months at room temperature and afford the coupling was used as coupling partner (Table 1, entries 17 and
products at essentially the same conversion rates and 18). About 95% of the coupling products was ob-
yields as freshly prepared catalyst solutions from pure tained with catalyst 1. While the product formation
1 and 2, respectively.[22]
Both complexes exhibit high activity in the catalytic coupling partner, 90 min were required with 1-ethyn-
coupling of terminal acetylenes with aryl iodides with- yl-2,4,5-trimethylbenzene. Sonogashira reactions per-
out the use of co-catalysts or other additives, under formed with sterically hindered and electronically de-
amine-free reaction conditions, and lead to high con- activated 1-iodo-2-methoxybenzene yielded 100% of
version rates and excellent yields at very low catalyst the coupling product within 30 min with catalyst 1
892
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Highly Convenient, Clean, Fast, and Reliable Sonogashira Coupling Reactions
FULL PAPERS
Table 1. Sonogashira cross-coupling reactions of aryl iodides with ethynylbenzene and 1-ethynyl-2,4,5-trimethylbenzene
(ethynyltrimethylbenzene) catalyzed by {C6H3-2,6-[XP(piperidinyl)2]2Pd(Cl)} (X=NH 1; X=O 2).[a]
Entry Aryl iodide
Alkyne
Cat. (ppm) Conv. [%][b] t [h]
TOF[c]
TON[d]
1
iodobenzene
iodobenzene
iodobenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
1 (50)
1 (0.5)
2 (50)
100
100
95
<0.25 >80,000 20,000
2[e]
3
6
1
333,333
19,000
2.0ꢁ106
19,000
4
5
6
iodobenzene
ethynyltrimethylbenzene 1 (50)
ethynylbenzene 1 (50)
ethynyltrimethylbenzene 1 (50)
100
100
94
100
92
92
92
100
95
100
97
100
100
96
92
100
48
100
100
100
96
96
75
<0.25 >80,000 20,000
<0.25 >80,000 20,000
4-iodomethoxybenzene
4-iodomethoxybenzene
4-iodoaniline
4-iodoaniline
4-iodoaniline
4-iodoaniline
4-iodophenol
4-iodophenol
2-iodotoluene
0.33
56,400
18,800
7
ethynylbenzene
ethynylbenzene
ethynylbenzene
1 (50)
1 (0.5)
2 (50)
<0.25 >80,000 20,000
8[e]
9
7
1
0.5
262,857
18,400
36,800
1.84ꢁ106
18,400
18,400
10
11
12
13
14[e]
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
ethynyltrimethylbenzene 1 (50)
ethynylbenzene 1 (50)
ethynyltrimethylbenzene 1 (50)
<0.25 >80,000 20,000
0.25 76,000 19,000
<0.25 >80,000 20,000
ethynylbenzene
ethynylbenzene
ethynylbenzene
1 (50)
1 (0.5)
2 (50)
2-iodotoluene
2-iodotoluene
2-iodotoluene
8
1
242,500
20,000
1.94ꢁ106
20,000
ethynyltrimethylbenzene 1 (50)
ethynylbenzene 1 (50)
ethynyltrimethylbenzene 1 (50)
<0.25 >80,000 20,000
2-iodobiphenyl
2-iodobiphenyl
2-iodomethoxybenzene
2-iodomethoxybenzene
2-iodomethoxybenzene
4-iodo-3-methylaniline
2-iodo-m-xylene
2-iodo-m-xylene
0.5
1.5
<0.5
1
38,400
12,267
>40,000 20,000
19,200
18,400
ethynylbenzene
ethynylbenzene
1 (50)
2 (50)
9,600
9,600
ethynyltrimethylbenzene 1 (50)
0.5
0.33
0.25
0.25
4
40,000
60,000
80,000
76,800
4,800
20,000
20,000
20,000
19,200
19,200
15,000
20,000
ethynylbenzene
1 (50)
ethynylbenzene
1 (50)
ethynyltrimethylbenzene 1 (50)
1 (50)
2-iodo-1,3-dimethoxybenzene ethynyltrimethylbenzene 1 (50)
2-iodo-1,3-dimethoxybenzene ethynylbenzene
6
3
2,500
6,667
2-iodothiophene
3-iodopyridine
3-iodopyridine
2-iodopyridine
ethynylbenzene
ethynylbenzene
1 (50)
1 (50)
100
100
100
96
<0.25 >80,000 20,000
<0.25 >80,000 20,000
ethynyltrimethylbenzene 1 (50)
ethynylbenzene 1 (50)
0.5
38,400
19,200
[a]
Reaction conditions: 2.0 mmol aryl halide, 2.2 mmol ethynylbenzene or 2.0 mmol 1-ethynyl-2,4,5-trimethylbenzene,
~2.2 mmolK3PO4, 4 mL ethylene glycol, catalyst added in solution (dioxane), reaction performed at 1408C.
Determined by GC/MS, based on aryl halide.
Defined as mol product per mol of catalyst per hour.
Defined as mol product per mol of catalyst.
[b]
[c]
[d]
[e]
Reactions were performed with 10 mmol of aryl halide and 10.5 mmol of ethynylbenzene in 12 mL of ethylene glycol.
(Table 1, entries 19 and 21). In contrast, only 48% of 26). Remarkably, even though a lower conversion rate
1-methoxy-2-(phenylethynyl)benzene was obtained was observed, complete product formation occurred
within 60 min when catalyst 2 was employed (Table 1, within only 3 h with 2-iodothiophene as coupling part-
entry 20). Even when 4-iodo-3-methylaniline was cou- ner (Table 1, entry 27). Quantitative formation of 3-
pled with ethynylbenzene, complete conversion was (phenylethynyl)pyridine and 3-[(2,4,5-trimethylphen-
achieved within 20 min with catalyst 1 (Table 1,
ACHTUNGTRENyNUGN l)ethynyl]pyridine, respectively, was achieved within
entry 22). Remarkably, 1,3-dimethyl-2-(phenylethy- only 15 min of reaction time, indicating that also sub-
nyl)benzene was exclusively and quantitatively strates with ligating properties, such as pyridines, are
formed within only 15 min when 2-iodo-m-xylene was compatible with the aminophosphine-based pincer-
coupled with ethynylbenzene or 1-ethynyl-2,4,5-trime- type Sonogashira catalysts (Table 1, entries 28 and
thylbenzene, respectively (Table 1, entries 23 and 24). 29). Indeed, complete conversion of 2-iodopyridine
A prolonged reaction time was required with the ster- and ethynylbenzene into 2-(phenylethynyl)pyridine
ically hindered and electronically deactivated 2-iodo- was achieved within only 30 min (Table 1, entry 30).
1,3-dimethoxybenzene. A reaction time of 4 h was The excellent performance of 1 was demonstrated fur-
needed to quantitatively convert 2-iodo-1,3-dimeth- ther in exemplary coupling reactions of phenyl iodide,
ACHTUNGTRENNUNGoxybenzene into 1,3-dimethoxy-2-(phenylethynyl)ben- 2-iodotoluene and 4-iodoaniline with ethynylbenzene
zene and 1-[(2,6-dimethoxyphenyl)ethynyl]-2,4,5-tri- in the presence of only 0.00005 mol% of catalyst.
methylbenzene, respectively (Table 1, entries 25 and Greater than 90% conversion was achieved in all
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893

Jeanne L. Bolliger and Christian M. Frech
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these reactions within less than 8 h of reaction time doaniline (Table 2, entries 1–4). On the other hand,
(Table 1, entries 2, 8 and 14). quantitative formation of 2-methoxy-6-[(2-methylphe-
In sharp contrast, when 2-ethynylpyridine was used nyl)ethynyl]naphthalene and 2-methoxy-6-[(2-me-
as coupling partner the formation of 2-(phenylethy- thoxyphenyl)ethynyl]naphthalene occurred within
nyl)pyridine was not observed. Instead, 2-(1,3-dioxo- only 30 and 90 min, respectively (Table 2, entries 5
lan-2-ylmethyl)pyridine was quantitatively formed. and 6). A similar yield but prolonged reaction time
The dramatic difference in reactivity of seemingly was necessary with sterically hindered 2-iodobiphenyl
similar substrate molecules was attributed to induc- as coupling partner (Table 2, entry 7). Reactions per-
tive effects of the functionalized alkyne: 2-ethynylpyr- formed with 2-iodo-1,3-dimethylbenzene gave 78% of
idine is readily attacked in a first step at the terminal 2-[(2,6-dimethylphenyl)ethynyl]-6-methoxynaphtha-
carbon atom of the ethynyl unit by ethylene glycol to lene within 90 min (Table 2, entry 8). Quantitative
yield 2-{[(E)-2-pyridin-2-ylethenyl]oxy}ethanol or 2- product formations were achieved after 30 and 60 min
{[(Z)-2-pyridin-2-ylethenyl]oxy}ethanol, respectively, with 3-iodopyridine as well as with 2-iodopyridine, re-
which react in a subsequent step selectively to 2-(1,3- spectively, as coupling partners (Table 2, entries 9 and
dioxolan-2-ylmethyl)pyridine (see Table 3, entries 6– 10). Remarkably, also reactions performed with 2-io-
10).[26] Catalysts are not required for this transforma- dothiophene yielded 2-[(6-methoxynaphthalen-2-yl)e-
tion as shown by reactions of 2-ethynylpyridine with thynyl]thiophene quantitatively after 4 h (Table 2,
ethylene glycol and K3PO4, which quantitatively yield- entry 11).
ed 2-(1,3-dioxolan-2-ylmethyl)pyridine within 5 min at
Furthermore, >95% conversion was generally ob-
1408C,[22] implying that Sonogashira cross-coupling re- tained within 1 hour when 5-ethynyl-1-methyl-1H-imi-
actions with 2-ethynylpyridines are not possible with dazole was coupled with iodobenzene, 2-iodotoluene,
ethylene glycol as solvent under these reaction condi- 2-iodobiphenyl and 2-iodo-m-xylene (Table 3, en-
tions. This is in contrast to 3-ethynylpyridine, which tries 1–4). Lower yields were noticed with 1-iodo-4-
undergoes smooth product formations, since a nucleo- methoxybenzene as coupling partner (Table 3,
philic attack on the terminal carbon atom is signifi- entry 5). On the other hand, significantly higher con-
cantly slower.
version rates were realized with 3-ethynylpyridine
In comparison with ethynylbenzene and 2,4,5-trime- (Table 3, entries 6–10).[26] In nearly all the reactions
thylbenzene, essentially the same yields but generally examined, >90% conversion was achieved within
lower conversion rates were noticed with 2-ethynyl-6- 30 min or less. Reactions performed with 4-iodoani-
methoxynaphthalene as coupling partner (Table 2). line only yielded 66% of the coupling product within
For instance, whereas quantitative product formation 1 hour.
was achieved with phenyl iodide within only 30 min
In comparison with aryl iodides, similar yields but
of reaction time with 0.005 mol% of 1 (and 5 h with generally lower conversion rates were observed when
0.5 ppm of catalyst 1), product yields of ~90% were aryl bromides were used as coupling partners
obtained after 120 min with the electronically deacti- (Table 4).[27] For example, whereas product yields of
vated substrates 1-iodo-4-methoxybenzene and 4-io- only ~70% were obtained after 3 and 4 h when
Table 2. Sonogashira cross-coupling reactions of aryl iodides with 2-ethynyl-6-methoxynaphthalene catalyzed by {[C6H3-2,6-
(NHP{piperidinyl}2)2]Pd(Cl)} (1).[a]
Entry
Aryl iodide
Alkyne
Cat. (ppm)
Conv. [%][b]
t [h]
TOF[c]
TON[d]
1
2
3
4
5
6
7
8
iodobenzene
iodobenzene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
1 (50)
1 (0.5)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
100
100
91
86
92
97
97
78
0.5
5
2
>40,000
400,000
9,100
20,000
2ꢁ106
18,200
17,200
18,400
19,400
19,400
15,600
20,000
20,000
20,000
4-iodoanisole
4-iodoaniline
2-iodotoluene
2-iodoanisole
2-iodobiphenyl
2-iodo-m-xylene
3-iodopyridine
2-iodopyridine
2-iodothiophene
2
8,600
0.5
1.5
3.5
1.5
0.5
1
36,800
12,933
5,543
10,400
>40,000
20,000
5,000
9
10
11
100
100
100
4
[a]
Reaction conditions: 2.0 mmol aryl halide, 2.0 mmol 2-ethynyl-6-methoxynaphthalene, 2.4 mmolK3PO4, 6 mL ethylene
glycol, catalyst added in solution (dioxane), reaction performed at 1408C.
Determined by GC/MS, based on aryl halide.
Defined as mol product per mol of catalyst per hour.
Defined as mol product per mol of catalyst.
[b]
[c]
[d]
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Highly Convenient, Clean, Fast, and Reliable Sonogashira Coupling Reactions
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Table 3. Sonogashira cross-coupling reactions of aryl iodides with 5-ethynyl-1-methyl-1H-imidazole and 3-ethynylpyridine
catalyzed by {[C6H3-2,6-(NHP{piperidinyl}2)2]Pd(Cl)] (1).[a]
Entry
Aryl iodide
Alkyne
Cat. (ppm)
Conv. [%][b]
t [h]
TOF[c]
TON[d]
1
2
3
4
5
6
7
8
9
iodobenzene
2-iodotoluene
2-iodobiphenyl
2-iodo-m-xylene
4-iodoanisole
iodobenzene
4-iodoanisole
4-iodoaniline
2-iodotoluene
2-iodoanisole
5-ethynyl-1-methyl-1H-imidazole
5-ethynyl-1-methyl-1H-imidazole
5-ethynyl-1-methyl-1H-imidazole
5-ethynyl-1-methyl-1H-imidazole
5-ethynyl-1-methyl-1H-imidazole
3-ethynylpyridine
3-ethynylpyridine
3-ethynylpyridine
3-ethynylpyridine
3-ethynylpyridine
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
1 (50)
100
100
97
96
44
97
91
66
100
98
1
1
1.5
1
2
0.25
0.5
1
0.25
0.5
20,000
20,000
13,333
19,200
4,400
77,600
36,400
13,200
>80,000
39,200
20,000
20,000
20,000
19,200
8,800
19,400
18,200
13,200
20,000
19,600
10
[a]
Reaction conditions: 2.0 mmol aryl halide, 2.2 mmol 5-ethynyl-1-methyl-1H-imidazole or 2.2 mmol 3-ethynylpyridine,
2.4 mmolK3PO4, 6 mL ethylene glycol, catalyst added in solution (dioxane), reaction performed at 1408C.
Determined by GC/MS, based on aryl halide.
Defined as mol product per mol of catalyst per hour.
Defined as mol product per mol of catalyst.
[b]
[c]
[d]
Table 4. Sonogashira cross-coupling reactions of aryl bromides with different alkynes catalyzed by {[C6H3-2,6-(NHP{piperidi-
nyl}2)2]Pd(Cl)} (1).[a]
Entry
Aryl bromide
Alkyne
Cat. (ppm)
Conv. [%][b]
t [h]
TOF[c]
TON[d]
1
2
3
4
5
6
7
8
bromobenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
ethynylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
ethynyltrimethylbenzene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
2-ethynyl-6-methoxynaphthalene
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
1 (100)
71
100
68
58
100
98
100
83
58
93
95
93
84
100
93
98
100
81
79
100
90
100
100
100
3
2
4
6
6
4
4
3
4
6
2
3
3
2
2
2
3
4
4
4
6
4
6
6
2,367
5,000
1,700
967
7,100
10,000
6,800
5,800
10,000
9,800
10,000
8,300
5,800
9,300
9,500
9,300
8,400
10,000
9,300
9,800
10,000
8,100
7,900
10,000
9,000
10,000
10,000
10,000
4-bromophenol
4-bromoaniline
2-bromotoluene
2-bromothiophene
3-bromopyridine
2-bromopyridine
bromobenzene
4-bromoanisole
4-bromoaniline
4-bromophenol
2-bromotoluene
2-bromo-m-xylene
3-bromopyridine
2-bromopyridine
2-bromothiophene
bromobenzene
4-bromoanisole
4-bromoaniline
2-bromotoluene
2-bromo-m-xylene
3-bromopyridine
2-bromopyridine
2-bromothiophene
1,667
2,450
2,500
2,767
1,450
1,550
4,750
3,100
2,800
5,000
4,650
4,900
3,333
2,025
1,975
2,500
1,500
2,500
1,667
1,667
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
[a]
Reaction conditions: 2.0 mmol aryl bromide, 3.0 mmol alkyne, 2.4 mmolK3PO4, 6 mL ethylene glycol, catalyst added in
solution (dioxane), reaction performed at 1408C.
Determined by GC/MS, based on aryl halide.
Defined as mol product per mol of catalyst per hour.
Defined as mol product per mol of catalyst.
[b]
[c]
[d]
phenyl bromide and 4-bromoaniline, respectively, 3-bromopyridine and 2-bromothiophene after 6 h and
À
were coupled with ethynylbenzene, complete C C less (Table 4, entries 1–7). Clean product formation
bond formation was observed with functionalized aryl and excellent conversion rates and yields were gener-
bromides, such as 4-bromophenol, 2-bromopyridine, ally observed with 1-ethynyl-2,4,5-trimethylbenzene
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Jeanne L. Bolliger and Christian M. Frech
FULL PAPERS
and 2-ethynyl-6-methoxynaphthalene as coupling coupling reaction. Generally no or low product yields
partners (Table 4, entries 8–24). Greater than 80% were observed when the reactions were performed in
yields of the coupling products were obtained within solvents of low polarity, such as dioxane, toluene or
6 h or less when bromobenzene, 4-bromoaniline, 4- p-xylene. Low yields in combination with large
bromophenol, sterically hindered 2-bromotoluene and amounts of various by-products were observed when
2-bromo-m-xylene as well as functionalized aryl bro- highly polar solvents, such as dimethyl sulfoxide
mides, such as 3-bromopyridine, 2-bromopyridine and (DMSO), dimethylformamide (DMF), N-methylpyr-
2-bromothiophene were coupled with 1-ethynyl-2,4,5- rolidone (NMP), ethanol or hexanol were used as re-
trimethylbenzene (Table 4, entries 8–16). Similarly, in action medium for Sonogashira reactions. The use of
almost all the reactions examined with 2-ethynyl-6- mixed solvent media did not improve the perfor-
methoxynaphthalene clean, quantitative product for- mance of the Sonogashira cross-coupling. Significant
mation was observed (Table 4, entries 17–24). Impres- sensitivity to base was noticed as well. Under other-
sive examples are reactions performed with 2-bromo- wise identical reaction conditions the change of base,
toluene and 2-bromo-m-xylene, as well as with 3-bro- such as NEt3, K2CO3, Na2CO3, NaHCO3, NaOH,
mopyridine, 2-bromopyridine and 2-bromothiophene, K3PO4, NaOAc and KO-t-Bu led to considerable vari-
respectively.[28] In contrast to the reactions examined
ACHTUNGTRENaNGNU tion in levels of conversion, isolated yields and by-
with aryl halides, no product formation was noticed product formation. However, only K2CO3 and K3PO4
with trifluoromethanesulfonates as coupling part- gave acceptable results with ethylene glycol, of which
ner.[29]
the latter reveals the cleaner transformations, higher
Overall, 1 and 2 belong nowadays to the most con- conversion rates and yields.
venient Sonogashira catalysts, since their preparation
Even though sigmoidal-shaped kinetics with induc-
is extremely simple, short and cheap. Moreover, 1 and tion periods between 3 and 5 min were observed with
2 remain stable in solution for several months at 1,[30] its transformation into palladium nanoparticles
room temperature and afford the coupling products appears to be unlikely, since the addition of up to 5%
at essentially the same conversion rates and yields as water (in order to promote the formation of palladi-
freshly prepared catalyst solutions from pure 1 and 2, um nanoparticles) to the reaction mixtures of exem-
respectively. Complex 1 and to a minor extent 2 plary Sonogashira reactions with phenyl iodide and
proved to be efficient and extremely reliable Sonoga- ethynylbenzene had no effect on the induction peri-
shira catalysts, which afford the coupling products ods but led to lower conversion rates.[31] This is in line
without the formation of homocoupled products or with the observation that the addition of tetrabuty-
other side-products within very short reaction times lammonium bromide, hexadecyltrimethylammonium
and at very low catalyst loadings with aryl iodides bromide or benzyltriethylammonium chloride (~10
under additive- and amine-free reaction conditions. mol%) – salts known to stabilize palladium nanoparti-
Furthermore, exclusion of air and moisture is not nec- cles – to catalytic reaction mixtures neither had an in-
essary. The catalysts remain highly active after the re- fluence on the conversion rates and the yields nor on
action is complete and catalysis is resumed at essen- the induction period.[30] Moreover, also the addition
tially the same rate upon addition of more substrates, of mercury to catalytic reaction mixtures had no
a first piece of evidence that palladium nanoparticles effect, thus suggesting that the catalytically active spe-
are not the catalytically active forms of 1 and 2, re- cies has a homogeneous nature.[32,33] Indeed, no differ-
spectively. Moreover, in contrast to most known cata- ence was noticed in either the conversion rates or
lysts, no excess of either substrate is required for the product yields when up to an equimolar amount (rela-
quantitative yield of the coupling products.[25]
tive to aryl iodide) of thiophene was added to the re-
The performance of the Sonogashira cross-coupling action mixtures.[34,35] Similarly, no effect was observed
reaction was found to be strongly temperature-depen- in the presence of up to an equimolar amount (rela-
dent, resulting in a dramatic drop in activity when the tive to catalyst) of triphenylphosphine, a further indi-
reaction temperature was lowered. For instance, reac- cation that palladium nanoparticles are not the cata-
tions performed with phenyl iodide and ethynylben- lytically active form of 1 and 2, respectively. On the
zene in ethylene glycol at 1208C in the presence of other hand, (partial) conversion of 1 (or 2) into an-
0.005 mol% of catalyst 1 quantitatively yield the cou- other catalytically active species, such as phosphorous
pling product within 2 h but only led to about 11% amidite- or phosphite-based Pd(II) or Pd(0) com-
À
conversion after 3 h at 1008C. 58% conversion into plexes (probably with the involvement of a Pd C
1,1’-ethyne-1,2-diyldibenzene was observed after 20 h. bond cleavage) most probably occurs under our cata-
Almost no activity was observed when the reactions lytic reaction conditions,[36] as indicated by the follow-
were performed below 808C (~4% conversion was ing experiment. When the aryl iodide and the alkyne
obtained after 20 h at 808C). Similarly, the change of were added to preheated reaction mixtures (6 min at
solvent had a dramatic influence on the product for- 1408C) of ethylene glycol, catalyst and base, instant
mation and conversion rate of the Sonogashira cross-
896
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Highly Convenient, Clean, Fast, and Reliable Sonogashira Coupling Reactions
FULL PAPERS
product formation occurred without indication Procedure for the “One-Pot” Synthesis of Catalyst
period.[29]
Solutions of 1 and 2
In conclusion, we have demonstrated that the ami-
nophosphine-based pincer complexes {[C6H3-2,6-
(XP{piperidinyl}2)2]Pd(Cl)} (X=NH 1; X=O 2) are
convenient, efficient and extremely reliable Sonoga-
shira catalysts, leading to very high conversion rates
and excellent yields for a large variety of substrates
with very low catalyst loadings (0.005 mol%). Lower
catalyst loadings lead to the same yields but slower
reactions. Ethylene glycol and K3PO4 were found to
be the ideal solvent and base for this transformation.
The catalyst preparation is extremely easy, short and
cheap. Catalyst solutions remain stable for several
months at room temperature and afford the coupling
products at essentially the same conversion rates and
yields as freshly prepared catalyst solutions from pure
1 and 2, respectively. Most important, the Sonogashira
reactions were carried out without exclusion of air
and moisture and without the use of amines, co-cata-
lysts, such as CuI, ZnCl2 or FeCl3 or other additives,
such as tetrabutylammonium bromide. Moreover,
since none of the starting materials are required in a
large excess for quantitative coupling, the present
system is very attractive for Sonogashira cross-cou-
pling reactions.
In a Young Schlenk tube 100 mg (0.35 mmol) of [Pd-
AHCTUNGTREG(NNUN cod)(Cl)2] were suspended with 50 mL of toluene. After the
addition of toluene solutions (20 mL) containing two equiv-
alents of 1,1’,1’’-phosphinetriyltripiperidine (198.5 mg;
0.70 mmol), the reaction mixture was stirred for 10 min.
Subsequently, an equimolar amount of resorcinol or 1,3-dia-
minobenzene, respectively, was added to these solutions.
The reaction mixtures were heated up to 1008C and stirred
until decolorization occurred. After the mixtures had been
cooled to room temperature and the insoluble reaction
products had been precipitated, the reaction mixtures were
filtered. Removal of the solvent and exctraction with diethyl
ether afforded the complexes in very high yields.[21a]
General Procedure for Sonogashira Cross-Coupling
Reactions of Aryl Iodides with Alkynes
All Sonogashira cross-coupling reactions were carried out
without rigorous exclusion of air and moisture. Ethylene
glycol was of reagent grade (98%) or better and used as re-
ceived. A Schlenk tube was charged with powdered K3PO4
and appropriate amounts of the aryl halide and alkyne (if
solid). The Schlenk tube was capped with a Teflon screw
cap, evacuated and backfilled with nitrogen. After addition
of ethylene glycol, the aryl halide and alkyne (if liquid), and
0.005 mol% of the catalyst (dissolved in dioxane) in a posi-
tive flow of nitrogen, the Schlenk tube was resealed and the
contents vigorously stirred at 1408C in an oil bath. Samples
taken from the reaction mixture were quenched with water,
extracted with ethyl acetate, and analyzed by GC/MS. At
the end of catalysis the reaction mixtures were allowed to
cool to room temperature, quenched with water (25 mL)
and extracted with ethyl acetate (2ꢁ40 mL). The combined
organic extracts were washed with 20 mL of water (or
20 mL of 1M Na2CO3 in reactions performed with 5-ethyn-
yl-1-methyl-1H-imidazole), dried (MgSO4) and evaporated
to dryness. The crude material was purified by flash chroma-
tography on silica gel.
Experimental Section
General Procedures
All synthetic operations for the catalyst preparation were
carried out in oven-dried glassware using a combination of
glove-box (M. Braun 150B-G-II) and Schlenk techniques
under a dinitrogen atmosphere. Solvents were reagent grade
or better, freshly distilled under an N2 atmosphere by stan-
dard procedures, and degassed by freeze-thaw cycles before
use. Deuterated solvents were purchased from Armar and
used as received. All the chemicals were purchased from Al-
drich Chemical Co., Acros Organics, or Fluka and used
without further purification.
1-[(4-Methoxyphenyl)ethynyl]-2,4,5-trimethylbenzene
(Table 1, entry 6)
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
1
3
Yield: 84%. H NMR (300 MHz, CD2Cl2): d=7.47 (d, J=
Analysis
3
8.9 Hz, 2H), 7.26 (s, 1H), 7.02 (s, 1H), 6.90 (d, J=8.9 Hz,
1H, and 13C{1H} NMR spectra were recorded at 300.00 and
75.42 MHz, respectively, on a Bruker ARX-300 spectrome-
ter. Chemical shifts (d) are expressed in parts per million
(ppm) coupling constants (J) are in Hz. The 1H and
13C NMR chemical shifts are reported relative to tetrame-
thylsilane; the resonance of the residual protons of the sol-
2H), 3.83 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H);
13C{1H} NMR (75 MHz, CD2Cl2): d=160.2, 137.7, 137.6,
134.4, 133.3, 133.0, 131.4, 121.0, 116.5, 114.6, 92.8, 87.8, 20.4,
19.9, 19.4; elemental analysis: calcd. for C18H18O: C 86.36, H
7.25; found: C 86.19, H 7.17.
1
vent was used as internal standard for H [d=5.32 (CD2Cl2);
4-[(2,4,5-Trimethylphenyl)ethynyl]aniline (Table 1,
entry 10)
4.78 and 3.30 (CD3OD)] and all-d solvent peaks for 13C [d=
53.8 (CD2Cl2); 49.0 (CD3OD)]. All measurements were car-
ried out at 298 K. Abbreviations used in the description of
NMR data are as follows: s, singlet; d, duplet; t, triplet; m,
multiplet. Elemental analyses were performed on a Leco
CHNS-932 analysator at the University of Zurich, Switzer-
land.
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/diethyl ether; 1:1) as a colorless
1
powder. Yield: 72%. H NMR (300 MHz, CD2Cl2): d=7.32
3
3
(d, J=8.7 Hz, 2H), 7.24 (s, 1H), 7.01 (s, 1H), 6.69 (d, J=
8.7 Hz, 2H), 3.88 (broad s, 2H), 2.43 (s, 3H), 2.25 (s, 3H),
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Jeanne L. Bolliger and Christian M. Frech
FULL PAPERS
2.23 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=147.2,
137.3, 136.9, 134.1, 132.9, 132.6, 131.0, 121.0, 114.9, 113.1,
93.3, 86.6, 20.1, 19.6, 19.1; elemental analysis: calcd. for
C17H17N: C 86.77, H 7.28, N 5.95; found: C 86.69, H 7.23, N
5.98.
1-[(2,6-Dimethylphenyl)ethynyl]-2,4,5-trimethyl-
benzene (Table 1, entry 24)
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
1
Yield: 86%. H NMR (300 MHz, CD2Cl2): d=7.36 (s, 1H),
7.20–7.11 (m, 3H), 7.07 (s, 1H), 2.59 (s, 6H), 2.53 (s, 3H),
2.30 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2):
d=140.3, 137.5, 137.3, 134.2, 133.0, 131.2, 127.8, 127.0, 123.8,
121.1, 97.7, 90.3, 21.4, 20.5, 19.7, 19.1; elemental analysis:
calcd. for C19H20: C 91.88, H 8.12; found: C 91.73, H 8.05.
4-[(2,4,5-Trimethylphenyl)ethynyl]phenol (Table 1,
entry 12)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether/hexane; 1:2) as a colorless
1
powder. Yield: 90%. H NMR (300 MHz, CD2Cl2): d=7.42
3
3
(d, J=8.8 Hz, 2H), 7.24 (s, 1H), 7.01 (s, 1H), 6.82 (d, J=
8.8 Hz, 2H), 5.16 (broad s, 1H), 2.42 (s, 3H), 2.25 (s, 3H),
2.22 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=156.0,
137.5, 137.4, 134.1, 133.2, 132.7, 131.1, 120.6, 116.4, 115.7,
92.5, 87.4, 20.1, 19.6, 19.0; elemental analysis: calcd. for
C17H16O: C 86.41, H 6.82; found: C 86.37, H 6.79.
1-[(2,6-Dimethoxyphenyl)ethynyl]-2,4,5-trimethyl-
benzene (Table 1, entry 26)
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:1) as a colorless powder.
1
Yield: 65%. H NMR (300 MHz, CD2Cl2): d=7.27 (s, 1H)
3
overlapped with 7.25 (t, J=8.4 Hz, 1H), 7.03 (s, 1H), 6.59
3
(d, J=8.4 Hz, 2H), 3.91 (s, 6H), 2.48 (s, 3H), 2.26 (s, 3H),
1,2,4-Trimethyl-5-[(2-methylphenyl)ethynyl]benzene
(Table 1, entry 16)
2.24 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=161.5,
137.7, 137.2, 134.0, 132.5, 131.1, 129.7, 121.1, 103.9, 102.4,
97.3, 85.3, 56.3 20.0, 19.7, 19.0; elemental analysis: calcd. for
C19H20O2: C 81.40, H 7.19; found: C 81.30, H 7.11.
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
1
Yield: 99%. H NMR (300 MHz, CD2Cl2): d=7.59–7.57 (m,
1H), 7.37 (s, 1H), 7.34–7.21 (m, 3H), 7.08 (s, 1H), 2.61 (s,
3H), 2.54 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR
(75 MHz, CD2Cl2): d=137.9 (2 overlapping signals), 135.3,
131.9, 130.7, 129.7, 128.9, 127.5, 126.0, 123.6, 121.7, 118.4,
90.8, 89.3, 18.8, 18.1, 17.4, 16.8; elemental analysis: calcd. for
C18H18: C 92.26, H 7.74; found: C 92.57, H 7.91.
3-[(2,4,5-Trimethylphenyl)ethynyl]pyridine (Table 1,
entry 29)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a colorless powder. Yield:
4
98%. 1H NMR (300 MHz, CD2Cl2): d=8.78 (dd, JA’C
=
=
=
=
4
2.1 Hz, 5JA’B =0.9 Hz, 1H), 8.53 (dd, 3JAB =4.9 Hz, JAC
4
1.7 Hz, 1H), 7.80 (ddd 3JCB =7.9 Hz, 4JCA’ =2.1 Hz, JCA
2-[(2,4,5-Trimethylphenyl)ethynyl]biphenyl (Table 1,
entry 18)
3
1.7 Hz, 1H), 7.30 (s, 1H), 7.29 (ddd, 3JBC =7.9 Hz , JBA
5
4.9 Hz, JBA’ =0.9 Hz, 1H), 7.04 (s, 1H), 2.47 (s, 3H), 2.26 (s,
3H), 2.24 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=
158.1, 154.4, 144.1, 143.7, 140.1, 138.9, 137.0, 129.1, 127.0,
125.6, 98.0, 95.0, 25.9, 25.6, 24.9; elemental analysis: calcd.
for C16H15N: C 86.84, H 6.83, N 6.33; found: C 86.65, H
6.75, N 6.47.
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
1
Yield: 84%. H NMR (300 MHz, CD2Cl2): d=7.75–7.70 (m,
3H), 7.54–7.37 (m, 6H), 7.18 (s, 1H), 7.00 (s, 1H), 2.27 (2
overlapping s, 6H), 2.54 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR
(75 MHz, CD2Cl2): d=143.9, 141.2, 137.7, 137.6, 134.1,
133.4, 133.0, 131.1, 129.9, 129.7, 128.6, 128.3, 127.8, 127.4,
122.5, 120.5, 92.3, 92.0, 20.0, 19.7, 19.1; elemental analysis:
calcd. for C23H20: C 93.20, H 6.80; found: C 93.11, H 6.83.
2-(1,3-Dioxolan-2-ylmethyl)pyridine
A Schlenk tube charged with 1 mmol 2-ethynylpyridine,
1 mmol K3PO4, and 2 mL ethylene glycol was placed in an
oil bath and the content stirred at 1408C for 5 min. After
addition of water (10 mL) the product was extracted with
ethyl acetate (2ꢁ15 mL). The combined organic extracts
were washed with water (20 mL), dried (MgSO4) and evapo-
rated to dryness giving the analytically pure 2-(1,3-dioxolan-
1-[(2-Methoxyphenyl)ethynyl]-2,4,5-trimethylbenzene
(Table 1, entry 21)
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as an orange oil,
which solidified upon standing. Yield: 91%. 1H NMR
(300 MHz, CD2Cl2): d=7.52–7.49 (m, 1H), 7.36–7.30 (m,
1H) overlapped with 7.30 (s, 1H), 7.05 (s, 1H), 7.00–6.93
(m, 2H), 3.92 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H), 2.25 (s,
3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=160.3, 137.8,
137.5, 134.2, 133.3, 132.8, 131.1, 129.8, 120.7, 113.3, 111.1,
93.0, 89.0, 56.0 20.1, 19.7, 19.1; elemental analysis: calcd. for
C18H18O: C 86.36, H 7.25; found: C 86.41, H 7.29.
2-ylmethyl)pyridine as
a pale yellow oil. Yield: 77%.
1H NMR (300 MHz, CD2Cl2): d=8.52–8.51 (m, 1H), 7.63–
7.57 (m, 1H), 7.26–7.24 (m, 1H), 7.15–7.11 (m, 1H), 5.25 (t,
3J=5.0 Hz, 1H), 3.96–3.92 (m, 2H), 3.84–3.79 (m, 2H), 3.12
3
(d, J=5.0 Hz, 2H); 13C{1H} NMR (75 MHz, CD2Cl2): d=
157.3, 149.5, 136.3, 124.3, 121.8, 104.2, 65.2, 43.5; elemental
analysis: calcd. for C9H11NO2: C 65.44, H 6.71, N 8.48;
found: C 65.25, H 6.61, N 8.71.
898
asc.wiley-vch.de
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Highly Convenient, Clean, Fast, and Reliable Sonogashira Coupling Reactions
FULL PAPERS
3
0.9 Hz, 1H), 7.76 (2 overlapping dublets, J=8.6 Hz, 2H),
7.62 (dd, 3J=8.4 Hz, 4J=1.6 Hz, 1H), 7.23–7.12 (m, 5H),
3.94 (s, 3H), 2.61 (s, 6H); 13C{1H} NMR (75 MHz, CD2Cl2):
d=158.7, 140.5, 134.5, 131.0, 129.5, 129.2, 128.9, 128.0, 127.2,
127.0, 123.4, 119.7, 119.0, 106.2, 98.8, 87.1, 55.6, 21.2; ele-
mental analysis: calcd. for C21H18O: C 88.08, H 6.34; found:
C 88.19, H 6.32.
2-Methoxy-6-[(4-methoxyphenyl)ethynyl]naphthalene
(Table 2, entry 3)
The title compound was obtained after flash chromatogra-
phy on silica gel (hexane/diethyl ether; 2:1) as a pale yellow
oil. Yield: 87%. 1H NMR (300 MHz, CD2Cl2): d=7.96 (d,
4J=1.0 Hz, 1H), 7.73 (2 overlapping dublets, 3J=8.5 Hz,
2H), 7.56–7.50 (m, 3H), 7.18–7.14 (m, 2H), 3.92 (s, 3H),
3.83 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=160.1,
158.7, 134.4, 133.3, 131.2, 129.6, 129.2, 128.9, 127.2, 119.7,
118.8, 115.7, 114.4, 106.1, 89.3, 88.8, 55.7 (2 overlapping sig-
nals); elemental analysis: calcd. for C20H16O2: C 83.31, H
5.59; found: C 83.29, H 5.61.
3-[(6-Methoxynaphthalen-2-yl)ethynyl]pyridine
(Table 2, entry 9)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a colorless powder. Yield:
90%. H NMR (300 MHz, CD2Cl2): d=8.78 (d, J=1.9 Hz,
1H), 8.53 (dd, 3J=4.9 Hz, 4J=1.6 Hz, 1H), 8.01 (d, 4J=
0.9 Hz, 1H), 7.84 (dt, 3J=7.9 Hz, 4J=1.9 Hz, 1H) 7.74 (2
1
4
4-[(6-Methoxynaphthalen-2-yl)ethynyl]aniline (Table
2, entry 4)
3
3
overlapping dublets, J=8.4 Hz, 2H), 7.56 (dd, J=8.4 Hz,
4J=1.6 Hz, 1H), 7.29 (ddd, 3J=7.9 Hz , 3J=4.9 Hz, 5J=
0.6 Hz, 1H), 7.20–7.16 (m, 2H), 3.92 (s, 3H); 13C{1H} NMR
(75 MHz, CD2Cl2): d=159.0, 152.5, 148.8, 138.5, 134.8,
131.8, 129.6, 129.0, 128.7, 127.3, 123.3, 120.8, 119.8, 117.7,
106.2, 93.3, 85.9, 55.6; elemental analysis: calcd. for
C18H13NO: C 83.38, H 5.05, N 5.40; found: C 83.27, H 4.99,
N 5.49.
The title compound was obtained after flash chromatogra-
phy on silica gel (hexane/ethyl acetate; 2:1) as a pale brown
powder. Yield: 78%. H NMR (300 MHz, CD2Cl2): d=7.93
1
4
3
(d, J=1.0 Hz, 1H), 7.73–7.70 (m, 2H), 7.52 (dd, J=8.5 Hz,
4J=1.7 Hz, 1H), 7.36 (d, 3J=8.6 Hz, 2H), 7.18–7.15 (m,
3
2H), 6.66 (d, J=8.6 Hz, 2H), 3.92 (s, 3H, overlapped with
broad s, 2H); 13C{1H} NMR (75 MHz, CD2Cl2): d=158.8,
147.6, 134.4, 133.3, 131.0, 129.6, 129.4, 129.1, 127.3, 119.8,
119.3, 115.0, 112.9, 106.4, 90.3, 88.0, 55.8; elemental analysis:
calcd. for C19H15NO: C 83.49, H 5.53, N 5.12; found: C
83.41, H 5.54, N 5.14.
2-[(6-Methoxynaphthalen-2-yl)ethynyl]pyridine
(Table 2, entry 10)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a pale yellow powder.
Yield: 89%. 1H NMR (300 MHz, CD2Cl2): d=8.62 (ddd,
2-Methoxy-6-[(2-methylphenyl)ethynyl]naph-
thalene (Table 2, entry 5)
4
5
4
3JAB =4.9 Hz, JAC =1.8 Hz, JAB’ =1.0 Hz, 1H), 8.06 (d, J=
3
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
0.8 Hz, 1H), 7.75 (2 overlapping doublets, J=8.5 Hz, 2H),
7.71–7.54 (m, 3H), 7.26–7.15 (m, 3H), 3.91 (s, 3H); 13C{1H}
NMR (75 MHz, CD2Cl2): d=159.1, 150.4, 143.9, 136.3,
134.9, 132.3, 129.7, 129.2, 128.7, 127.4, 127.3, 123.0, 119.8,
117.4, 106.2, 89.7, 88.9, 55.7; elemental analysis: calcd. for
C18H13NO: C 83.38, H 5.05, N 5.40; found: C 83.21, H 5.17,
N 5.31.
1
4
Yield: 89%. H NMR (300 MHz, CD2Cl2): d=7.99 (d, J=
3
1.0 Hz, 1H), 7.74 (2 overlapping dublets, J=8.1 Hz, 2H),
7.56 (dd, 3J=8.4 Hz, 4J=1.6 Hz, 1H), 7.53 (d, 3J=6.3 Hz,
1H), 7.28–7.24 (m, 2H), 7.22–7.18 (m, 2H), 7.17 (s, 1H),
3.92 (s, 3H), 2.56 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2):
d=158.8, 140.5, 134.5, 132.0, 131.3, 129.8, 129.6, 129.2, 128.9,
128.6, 127.2, 126.0, 123.5, 119.7, 118.7, 106.2, 94.3, 88.3, 55.6,
20.9; elemental analysis: calcd. for C20H16O: C 88.20, H
5.92; found: C 88.17, H 5.91.
2-[(6-Methoxynaphthalen-2-yl)ethynyl]thiophene
(Table 2, entry 11)
The title compound was obtained after flash chromatogra-
phy on silica gel (hexane/diethyl ether 4:1) as a colorless
2-[(6-Methoxynaphthalen-2-yl)ethynyl]biphenyl
(Table 2, entry 7)
1
powder. Yield: 94%. H NMR (300 MHz, CD2Cl2): d=7.98
(d, 4J=0.8 Hz, 1H), 7.74 (2 overlapping doublets, 3J=
8.8 Hz, 3J=8.4 Hz, 2H), 7.55 (dd, 3J=8.4 Hz, 4J=1.7 Hz,
1H), 7.36–7.35 (m, 2H), 7.19 (dd, 3J=8.8 Hz, 4J=2.6 Hz,
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a colorless powder. Yield:
1
4
94%. H NMR (300 MHz, CD2Cl2): d=7.82 (broad s, 1H),
1H), 7.16 (d, J=2.4 Hz, 1H), 7.07–7.08 (m, 1H), 3.92 (s,
3H); 13C{1H} NMR (75 MHz, CD2Cl2): d=158.9, 134.6,
132.2, 131.3 129.6, 128.9, 128.7, 127.6 (2 overlapping signals),
127.3, 123.7, 119.8, 118.0, 106.1, 93.9, 82.4, 55.7; elemental
analysis: calcd. for C17H12OS: C 77.24, H 4.58; found: C
77.06, H 4.66.
7.77–7.67 (m, 5H), 7.57–7.36 (m, 7H), 7.19–7.14 (m, 2H),
7.17 (s, 1H), 3.92 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2):
d=158.8, 144.1, 141.0, 134.5, 133.1, 131.2, 129.8, 129.7, 129.5,
128.9, 128.8, 128.7, 128.3, 127.9, 127.5, 127.1, 122.0, 119.7,
118.5, 106.2, 93.0, 89.3, 55.6; elemental analysis: calcd. for
C25H18O: C 89.79, H 5.43; found: C 89.88, H 5.48.
1-Methyl-5-[(2-methylphenyl)ethynyl]-1H-imidazole
(Table 3, entry 2)
2-[(2,6-Dimethylphenyl)ethynyl]-6-methoxynaph-
thalene (Table 2, entry 8)
The title compound was obtained after flash chromatogra-
phy on silica gel (CH2Cl2/methanol 3:1) as a pale yellow
powder. Yield: 95%. 1H NMR (300 MHz, MeOH-d4): d=
7.49 (s, 1H), 7.28–7.26 (m, 1H), 7.08–6.96 (m, 4H), 3.53 (s,
The title compound was obtained after flash chromatogra-
phy on silica gel (toluene/hexane; 1:2) as a colorless powder.
1
4
Yield: 66%. H NMR (300 MHz, CD2Cl2): d=8.03 (d, J=
Adv. Synth. Catal. 2009, 351, 891 – 902
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899

Jeanne L. Bolliger and Christian M. Frech
FULL PAPERS
4
3H), 2.28 (s, 3H); 13C{1H} NMR (75 MHz, MeOH-d4): d=
140.8, 140.0, 133.6, 132.5, 130.6, 129.9, 126.8, 123.3, 117.9,
96.4, 81.5, 32.5, 21.0; elemental analysis: calcd. for C13H12N2:
C 79.56, H 6.16, N 14.27; found: C 79.42, H 6.13, N 14.19.
83%. 1H NMR (300 MHz, CD2Cl2): d=8.75 (dd, JA’C
=
=
=
4
2.1 Hz, 5JA’B =0.9 Hz, 1H), 8.52 (dd, 3JAB =4.9 Hz, JAC
4
1.7 Hz, 1H), 7.82 (ddd, 3JCB =7.9 Hz, 4JCA’ =2.1 Hz, JCA
1.7 Hz, 1H), 7.52–7.49 (m, 1H), 7.39–7.32 (m, 1H), 7.28
3
3
5
(ddd, JBC =7.9 Hz , JBA =4.9 Hz, JBA’ =0.9 Hz, 1H), 6.99–
6.94 (m, 2H), 3.92 (s, 3H); 13C{1H} NMR (75 MHz, CD2Cl2):
d=160.5, 152.4, 148.8, 138.4, 133.7, 130.7, 123.3, 120.9, 120.8,
112.0, 111.2, 90.0, 89.3, 56.1; elemental analysis: calcd. for
C14H11NO: C 80.36, H 5.30, N 6.69; found: C 80.25, H 5.36,
N 6.65.
5-(Biphenyl-2-ylethynyl)-1-methyl-1H-imidazole
(Table 3, entry 3)
The title compound was obtained after flash chromatogra-
phy on silica gel (CH2Cl2 with 10% methanol) as a pale
1
yellow oil. Yield: 79%. H NMR (300 MHz, MeOH-d4): d=
7.49–7.38 (m, 4H), 7.32–7.19 (m, 6H), 7.00 (s, 1H), 3.21 (s,
3H); 13C{1H} NMR (75 MHz, MeOH-d4): d=145.0, 141.9,
139.8, 133.6, 133.3, 130.6, 130.2, 129.9, 129.1, 128.6, 128.3,
122.1, 117.8, 97.3, 80.5, 32.3; elemental analysis: calcd. for
C18H14N2: C 83.69, H 5.46, N 10.84; found: C 83.54, H 5.52,
N 10.87.
References
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1-Methyl-5-[(2,6-dimethylphenyl)ethynyl]-1H-imid-
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The title compound was obtained after flash chromatogra-
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1
yellow powder. Yield: 88%. H NMR (300 MHz, MeOH-d4):
d=7.56 (s, 1H), 7.15 (s, 1H), 7.05–6.94 (m, 3H), 3.63 (s,
3H), 2.35 (s, 6H); 13C{1H} NMR (75 MHz, MeOH-d4): d=
140.9, 139.9, 133.4, 129.3, 127.8, 123.1, 118.1, 95.1, 85.9, 32.6,
21.3; elemental analysis: calcd. for C14H14N2: C 79.97, H
6.71, N 13.32; found: C 79.89, H 6.69, N 13.40.
5-[(4-Methoxyphenyl)ethynyl]-1-methyl-1H-imidazole
(Table 3, entry 5)
The title compound was obtained after flash chromatogra-
phy on silica gel (CH2Cl2 with 10% methanol) as a yellow
powder. Yield: 36%. 1H NMR (300 MHz, MeOH-d4): d=
3
7.60 (s, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.13 (s, 1H), 6.86 (d,
3J=8.9 Hz, 2H), 3.75 (s, 3H), 3.67 (s, 3H); 13C{1H} NMR
(75 MHz, MeOH-d4): d=161.6, 139.7, 133.9, 133.2, 118.1,
115.5, 115.2, 97.4, 75.8, 55.8, 32.3; elemental analysis: calcd.
for C13H12N2O: C 73.57, H 5.70, N 13.20; found: C 73.51, H
5.72, N 13.26.
[3] Other methods for the preparation of arylated acety-
lenes include the variation of a Negishi-type coupling,
which uses zinc(II) acetylides which are prepared first
from acetylenes, a base (e.g., BuLi, LDA) and ZnCl2 in
at least quantitative amounts, which are then cross-cou-
pled with aryl halides in the presence of a palladium-
phosphine catalyst.[4].
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4-(Pyridin-3-ylethynyl)aniline (Table 3, entry 8)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a colorless powder. Yield:
58%. 1H NMR (300 MHz, CD2Cl2): d=8.70 (dd, JA’C
=
=
=
=
4
2.1 Hz, 5JA’B =0.9 Hz, 1H), 8.48 (dd, 3JAB =4.9 Hz, JAC
4
1.7 Hz, 1H), 7.77 (ddd, 3JCB =7.9 Hz, 4JCA’ =2.1 Hz, JCA
4
1.7 Hz, 1H), 7.34 (d, 3J=8.7 Hz, 2H), 7.26 (ddd, JBC
3
7.9 Hz , 3JBA =4.9 Hz, 5JBA’ =0.9 Hz, 1H), 6.65 (m, 3J=
8.7 Hz, 2H), 3.99 (broad s, 2H); 13C{1H} NMR (75 MHz,
CD2Cl2): d=152.2, 148.3, 147.9, 138.2, 133.3, 123.3, 121.3,
114.8, 111.6, 93.7, 84.2; elemental analysis: calcd. for
C13H10N2: C 80.39, H 5.19, N 14.42; found: C 80.22, H, 5.21,
N 14.30.
3-[(2-Methoxyphenyl)ethynyl]pyridine (Table 3,
entry 10)
The title compound was obtained after flash chromatogra-
phy on silica gel (diethyl ether) as a colorless oil. Yield:
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900
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 891 – 902

Highly Convenient, Clean, Fast, and Reliable Sonogashira Coupling Reactions
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[12] For copper-free Sonogashira reactions, see, for exam-
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Adv. Synth. Catal. 2009, 351, 891 – 902
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
901

Jeanne L. Bolliger and Christian M. Frech
FULL PAPERS
[16] For a selected paper on the palladium/phosphine-free
ligand/CuI/amine system, see: R. A. Batey, M. Shen, A.
Lough, Org. Lett. 2002, 4, 1411.
[17] For papers on TBAF as an activator for the palladium-
catalyzed Sonogashira reaction, see, for example: a) A.
Mori, J. Kawashima, T. Shimada, M. Suguro, K. Hira-
bayashi, Y. Nishihara, Org. Lett. 2000, 2, 2935; b) A.
Mori, T. Shimada, T. Kondo, A. Sekiguchi, Synlett 2001,
649.
[18] Despite the critical role of copper acetylides in cataly-
sis, upon exposure to air or any oxidizing agents the
copper acetylide species also undergo homocoupling,
yielding in side-products (Glaser coupling).[19] More-
over, the extremely high reactivity and the explosive
nature of the copper acetylides make the Sonogashira
reaction sensitive to air and moisture.[1d,19,20]
of homocoupling was observed in some of the reactions
performed with aryl bromides. Thus, in order to maxi-
mize the product yields the reactions were generally
performed with 1.5 equivalents (relative to aryl bro-
mide) of alkyne.
[28] Coupling reactions performed with 3-ethynylpyridine
and 5-ethynyl-1-methyl-1H-imidazole and aryl bro-
mides as coupling partners were only of limited success,
since the formation of side-products, such as 3-(1,3-di-
oxolan-2-ylmethyl)pyridine became dominant.
[29] Aryl trifluoromethanesulfonates are sensitive towards
moisture and hence, are expected to be incompatible
with our reaction protocol. Indeed, no coupling prod-
ucts were formed, clean conversions into their corre-
sponding phenols occurred instead.
[30] See graph S1 in the Supporting Information.
[31] If palladium nanoparticles were the catalytically active
form of 1 (and 2), the presence of water in the reaction
mixtures of the Sonogashira reaction should lead to
shorter induction periods when compared with anhy-
drous reaction conditions.[21b] The reason for the effect
of water on the induction period could be explained by
a faster decomposition of the pincer core. However, no
effect on the induction period was noticed. The addi-
tion of large amounts of water (~10%), however, could
result in the partial decomposition of the catalyst and
would provide an explanation for the slower conver-
sions observed.
[19] P. Siemsen, R. C. Livingston, F. Diederich, Angew.
Chem. 2000, 112, 2740; Angew. Chem. Int. Ed. 2000, 39,
2632.
[20] a) H. Doucet, J.-C. Hierso, Angew. Chem. 2007, 119,
850; Angew. Chem. Int. Ed. 2007, 46, 834; b) E. Ne-
gishi, L. Anastasia, Chem. Rev. 2003, 103, 1979; c) K.
Sonogashira, J. Organomet. Chem. 2002, 653, 46; d) S.
Thorand, N. Krause, J. Org. Chem. 1998, 63, 8551.
[21] a) J. L. Bolliger, O. Blacque, C. M. Frech, Angew.
Chem. 2007, 119, 6634; Angew. Chem. Int. Ed. 2007, 46,
6514; b) J. L. Bolliger, O. Blacque, C. M. Frech, Chem.
Eur. J. 2008, 14, 7969.
[22] See Experimental Section.
[32] For a comprehensive review article about the problem
of distinguishing true homogeneous catalysis from solu-
ble or other metal-particle heterogeneous catalysis
under reducing conditions see: J. A. Widegren, R. G.
Finke, J. Mol. Catal. A 2003, 198, 317 and references
cited therein.
[33] a) K. Yu, W. Sommer, J. M. Richardson, M. Weck,
C. W. Jones, Adv. Synth. Catal. 2005, 347, 161; b) K. Yu,
W. Sommer, M. Weck, C. W. Jones, J. Catal. 2005, 226,
101; c) D. E. Bergbreiter, P. L. Osburn, J. D. Frels, Adv.
Synth. Catal. 2005, 347, 172; d) M. R. Eberhard, Org.
Lett. 2004, 6, 2125.
[34] This result was expected to be obtained, since 2-iodo-
thiophene was successfully coupled with ethynylben-
zene and 2-ethynyl-6-methoxynaphthalene (see Table 1,
entry 24 and Table 2, entry 10).
[35] The addition of CS2 to catalytic reaction mixtures is
not appropriate, due to catalyst degradation involving
[23] No difference in the performance of the Sonogashira
reaction was observed when ethylene glycol of various
qualities (with up to 5% of water) was used.
[24] Note that only recently reports on Sonogashira cross-
coupling reactions in air and (mixed) aqueous media
have appreared a) C. Wolf, R. Lerebours, Org. Biomol.
Chem. 2004, 2, 2161; b) L. Ray, S. Barman, M. M.
Shaikh, P. Ghosh, Chem. Eur. J. 2008, 14, 6646.
[25] Since the boiling point of ethynylbenzene is 1428C and
hence, only slightly above the reaction temperature
(1408C), reactions with ethynylbenzene were per-
formed with 1.1 equiv. (relative to aryl iodide) to
assure complete product formation within 15 min. Simi-
larly, in reactions with 3-ethynylpyridine a slight excess
(1.1 equiv. relative to aryl iodide) was added as well.[26]
[26] It should be mentioned that also 3-ethynylpyridine un-
dergoes slow formation of 3-(1,3-dioxolan-2-ylmethyl)-
pyridine with ethylene glycol under catalytic reaction
conditions. This side-reaction, however, only lead to
significant amounts of 3-(1,3-dioxolan-2-ylmethyl)pyri-
dine in slow Sonogashira cross-coupling reactions, as it
is for instance the case when 4-iodoaniline (see Table 3,
entry 8) was used as coupling partner, explaining the
relatively low product yield obtained.
À
P N bond cleavage and (partial) formation of the
bis(piperidine-1-carbodithioato)palladium
complex
[Pd(S2CNpiperidyl)2].[21b].
[36] It should be noted that NMR investigations were not
conclusive and the transformation of 1 (or 2) into an-
other, catalytically active species could not be con-
firmed by NMR spectroscopy.
[27] In contrast to reactions examined with aryl iodides,
where no side-products were detectable, small amounts
902
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Adv. Synth. Catal. 2009, 351, 891 – 902