First Application of Secondary Phosphines as Supporting Ligands for the Palladium-Catalyzed Heck Reaction: Efficient Activation of Aryl Chlorides

Article abstract of DOI:10.1002/1615-4169(200207)344:5<495::AID-ADSC495>3.0.CO;2-6

Secondary dialkylphosphines were successfully used for the first time as efficient supporting ligands for the palladium-catalyzed Heck reaction of electron-rich and electron-poor aryl chlorides with olefins such as acrylate, ethylene, styrene, and n-butyl vinyl ether. The yields with HP(t-butyl)₂ and HP(adamantyl)₂ were comparable or better than those obtained with known systems of tertiary phosphines such as P(cyclohexyl)₃ and P(t-butyl)₃, especially at a catalyst loading of < 1 mol %. In comparison with tertiary phosphines, the secondary phosphines have the advantage of being readily available at low cost on a technical scale, and are comparable with respect to handling and oxygen sensitivity.

Full text of DOI:10.1002/1615-4169(200207)344:5<495::AID-ADSC495>3.0.CO;2-6

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First Application of Secondary Phosphines as Supporting Ligands
for the Palladium-Catalyzed Heck Reaction: Efficient Activation
of Aryl Chlorides
Anita Schnyder, Thomas Aemmer, Adriano F. Indolese, Ulrich Pittelkow,
Martin Studer*
Solvias AG, Klybeckstrasse 191, Postfach, 4002 Basel, Switzerland.
Fax: ( ‡ 41)-61-686-6311, e-mail: martin.studer@solvias.com
Received: February 19, 2002; Accepted: March 28, 2002
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/
acrylate using a Chemspeed parallel synthesizer. Be-
Abstract: Secondary dialkylphosphines were suc-
sides tertiary phosphines, also secondary phosphines
cessfully used for the first time as efficient support-
were included.[4] Surprisingly, the palladium complexes
ing ligands for the palladium-catalyzed Heck reac-
of secondary dialkylphosphines gave highly active
tion of electron-rich and electron-poor aryl chlorides
catalytic systems that were as efficient or better than
with olefins such as acrylate, ethylene, styrene, and
those with tri-t-butylphosphine or tricyclohexylphos-
n-butyl vinyl ether. The yields with HP(t-butyl)2 and
phine, and the liquid secondary phosphines were com-
HP(adamantyl)2 were comparable or better than
parable to tertiary phosphines with respect to handling
those obtained with known systems of tertiary
and oxygen sensitivity.
phosphines such as P(cyclohexyl)3 and P(t-butyl)3,
Secondary phosphines like HPNor2 or 1 are easily
especially at a catalyst loading of <1 mol %. In
synthesized from PH3 and the corresponding olefins,
comparison with tertiary phosphines, the secondary
and are available in bulk quantities at a relatively low
phosphines have the advantage of being readily
price.[5] Reports about the application of such ligands in
available at low cost on a technical scale, and are
transition metal catalysis are very rare,[6] and no
comparable with respect to handling and oxygen
example is known for palladium-catalyzed reactions
sensitivity.
with aryl halides. Here we describe the first application
of secondary phosphines as supporting ligands for a
Keywords: arylation; C-C coupling; Heck reaction;
palladium-catalyzed reaction.
palladium; secondary phosphine
To demonstrate the efficiency of the secondary
phosphines as ligands in the Heck reaction, we reacted
butyl acrylate with the highly deactivated 4-chloroani-
sole as model substrate (Table 1). As Pd source, we used
The palladium-catalyzed Heck reaction of aryl halides is a 20% PdCl2 solution in concentrated HCl. With
an important method in organic synthesis, and many 1 mol % Pd, the best secondary phosphines were
new catalysts have been developed in order to allow new slightly less active than P(t-Bu)3, but significantly better
transformations, to expand the scope of the reaction, use than PCy3. When we tried to lower the catalyst loading
cheaper starting materials, or to improve the catalytic to 0.5 mol %, the reaction was often not reproducible.
activity.[1] One crucial factor for a successful catalytic Replacing PdCl2 by Pd(OAc)2 solved this problem and
system is the choice of the ligand, and most frequently at a catalyst loading of 0.5 mol %, the palladium
tertiary phosphines are used. The activation of aryl
chlorides was studied intensely by several research
groups in recent years.[2] Up to now, sterically hindered
and electron-rich tertiary phosphines were the most
successful ligands for the Heck reaction.[3] Despite
considerable progress, the catalyst activity for the
Heck reaction of aryl chlorides is still too low and
improved systems are urgently needed.
In search of such new systems, we screened a wide
variety of supporting ligands for the Heck reaction of 4-
chloroanisole and 4-chlorobenzotrifluoride with butyl reaction.
Figure 1. Secondary phosphine ligands used for the Heck
Adv. Synth. Catal. 2002, 344, No. 5
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1615-4150/02/34405-495 498 $ 17.50+.50/0
495

Anita Schnyder et al.
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Table 1. Yields of butyl 4-methoxycinnamate in the Heck
reaction of 4-chloroanisole with butyl acrylate using palla-
dium complexes with different phosphines.[a]
complexes of HP(t-Bu)2 and HPAd2 gave yields com-
parable to the Pd-complex of P(t-Bu)3, one of the most
efficient systems currently known.[4a]
Since HPAd2 showed the best performance, the scope
of this secondary phosphine in the Heck reaction was
investigated (Table 2). At a catalyst loading of 2 mol %,
80 100% conversion was observed with a wide variety
of electron-poor and electron-rich aryl chlorides (En-
tries 1 9). ortho-Substituted aryl chlorides were also
successfully coupled. However, they gave lower yields
and required higher amounts of catalyst (Entries 10 and
11).
Entry
Ligand
GC Yields [%][a]
[b]
[c]
PdCl2
Pd(OAc)2
(1 mol %)
(0.5 mol %)
Heteroaryl chlorides were tested with mixed success.
3-Chloropyridine reacted smoothly with butyl acrylate
(Entry 12), but 2-chloropyridine gave low conversion.
In this case, the main product was the homo-coupled
2,2'-bipyridyl (Entry 13). For unknown reasons, no
reaction was observed with 2-chloropyrimidine (En-
try 14). With 2-chlorothiophene the conversion was
fairly high, however, the product was isolated in only
15% yield, probably due to instability (Entry 15). Other
olefins such as butyl vinyl ether, styrene, and ethylene
were also successfully reacted with 4-chlorotoluene
(Entries 16 18).
1
2
3
4
5
6
7
8
PCy3
40
98
39
86
77
78
24
64
15
49
17
53
52
34
0
P(t-Bu)3
HPCy2
HP(t-Bu)2
HPAd2
HPNor2
1
2
27
[a]
For reaction conditions, see experimental section and
supporting information.
Yields determined by GLC after 20 hours (internal
standard method).
[b]
[c]
Average of two runs.
Table 2. Scope of the Heck reaction with HPAd2 as the ligand.[a]
Entry
Chloroarenes
Olefins[b]
Conversion [%][c]
Isolated yield [%]
1
2
3
4
5
4-chlorobenzaldehyde
4-chloroacetophenone
4-chloronitrobenzene
3-chlorodimethylaniline
ethyl 3-chlorobenzoate
1-chloro-4-(trifluoromethyl)benzene
chlorobenzene
A
A
A
A
A
A
A
100
100
100
100
100
80
71
66
82
90
55 (18)[d]
6
7
76
98
75[e]
8
4-chlorotoluene
A
93
87
9
4-chloroanisole
A
A
A
A
A
A
A
B
89
84
57
100
53
0
87
94
76
71
50
38
10
11
12
13
14
15
16
17
18
2-chlorobenzonitrile[f]
1-chloronaphthalene
3-chloropyridine
84
2-chloropyridine[f]
10 (31)[g]
2-chloropyrimidine
2-chlorothiophene
4-chlorotoluene[f, h]
4-chlorotoluene
22
74[i]
79
styrene
4-chlorotoluene
ethylene[j]
94
70[e]
[a]
For reaction conditions see experimental section and supporting information.
A: butyl acrylate; B: butyl vinyl ether.
Conversion was determined by GLC (internal standard).
In parentheses: isolated yield of butyl 3,3-diarylacrylate.
Purified by distillation.
With 4 mol % catalyst.
In parentheses: isolated yield of 2,2'-bipyridyl.
With KOAc as base.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
Isolated yields of all Heck products. According to GLC, the reaction mixture contained 40% E, 15% Z, and 19%
p-methylacetophenone.
With 30 bar ethylene.
[j]
496
Adv. Synth. Catal. 2002, 344, 495 498

Secondary Phosphines as Supporting Ligands for Pd-Catalyzed Heck Reaction
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(silica gel, mixtures of EtOAc/hexanes as eluent). For details,
see supporting information.
The high efficiency of the secondary phosphines is
surprising, since secondary phosphines have a much
lower basicity and are less sterically hindered than P(t-
Bu)3. According to the results of Littke and Fu[3c] this
should drastically decrease the activity of the catalyst
and raises of course questions about the nature of the
active palladium catalyst. Various explanations are
possible: Even though mononuclear palladium com-
plexes with secondary phosphine ligands are known,[7]
palladium can also form phosphido-bridged di- and
polynuclear compounds.[8] Moreover, it is well known
that secondary phosphines react with aryl halides in the
presence of palladium catalysts to form aryl phos-
phines.[9] Under the reaction conditions, this would
result in a Pd complex with a tertiary phosphine of the
Acknowledgements
This work was supported by the Novartis Forschungsstiftung.
We thank our colleagues Hans-Ulrich Blaser and Benoit Pugin
(Solvias AG), Matthias Beller and Wolfgang M‰gerlein (IfOK,
Rostock, Germany) for general discussion, and Lars Troendlin
and Andrea Marti for there careful experimental work. Com-
pounds 1 and 2 were generously provided by CytecIndustries,
Niagara Falls, USA (Al Robertson and Olivier Rouher).
Alkyl2P-Aryl type. Last but not least, the secondary References and Notes
phosphines might react with the butyl acrylate in a
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In conclusion, we have reported the first palladium-
catalyzed reaction with secondary phosphines as sup-
porting ligands. The activity of these catalysts is
comparable with the best systems known up to date
for the Heck reaction of aryl chlorides. The secondary
phosphines are commercially available in bulk quanti-
ties at a relatively low price. Therefore, they are an
interesting alternative to the tertiary phosphines as
ligands for technical applications. Moreover, the rich
complex chemistry of secondary phosphines opens up a
totally new field of opportunities for the transition metal
catalysis since they display a much more diverse
coordination chemistry than tertiary phosphines.
Experimental Section
For a detailed description of the experiments, see supporting
information.
[4] HPCy2 and HP(t-Bu)2 were obtained from Strem Chem.
Co.; HPNor2, 1, and 2 were obtained from Cytec Chem.
Co.; HPAd2 was synthesized according to J. R. Goerlich,
R. Schmutzler, Phosphorus, Sulfur, and Silicon 1995, 102,
211.
General Procedure for the Experiments in Tables 1
and 2
To Na2CO3 (0.81 g, 7.6 mmol) and diadamantylphosphine
(60.6 mg, 0.2 mmol) in a 50-mL Schlenk tube under argon,
DMA (N,N-dimethylacetamide, 4 mL), the chloroarene
(5 mmol), and n-butyl acrylate (0.70 g, 5.5 mmol) were added
and the reaction mixture was heated in a oil bath to 140 8C.
After 5 minutes, the catalyst solution [0.1 mmol Pd(II) in
0.4 mL DMA prepared by diluting 53 mg of a 20% Pd (w/w)
solution in concentrated HCl with 0.35 mL DMA, or by
dissolving 22 mg Pd(OAc), in 0.4 mL DMF]. The reaction
mixture was stirred for additional 20 hours at 140 8C oil bath
temperature. After cooling to room temperature, the reaction
mixture was poured into water, and extracted twice with t-butyl
methyl ether. The organic phases were washed with water,
dried over Na2SO4, and concentrated under reduced pressure.
The crude material was purified by column chromatography
[5] Personal communication for O. Rouher and A. Robert-
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