A new efficient tetraphosphine/palladium catalyst for the Heck reaction of aryl halides with styrene or vinylether derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00219-8

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C ₃H₅)]₂ system efficiently catalyses the Heck reaction of aryl halides with styrene and vinylether derivatives. High turnover numbers can be obtained for the reaction of several aryl halides with styrene and styrene derivatives. Lower turnover numbers have been observed in the presence of vinylethers.

Full text of DOI:10.1016/S0040-4039(02)00219-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2191–2194
A new efficient tetraphosphine/palladium catalyst for the Heck
reaction of aryl halides with styrene or vinylether derivatives
Marie Feuerstein, Henri Doucet* and Maurice Santelli*
Laboratoire de Synthe`se Organique associe´ au CNRS, Faculte´ des Sciences de Saint Je´roˆme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 26 November 2001; accepted 29 January 2002
Abstract—cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C3H5)]2 system efficiently catalyses the Heck
reaction of aryl halides with styrene and vinylether derivatives. High turnover numbers can be obtained for the reaction of several
aryl halides with styrene and styrene derivatives. Lower turnover numbers have been observed in the presence of vinylethers.
© 2002 Elsevier Science Ltd. All rights reserved.
The Heck reaction is one of the most widely used
palladium-catalysed methodologies in organic synthe-
sis.1 The efficiency of several catalysts for the reaction
of aryl halides with acrylates has been studied in detail.2
On the other hand, the reaction in the presence of
styrene and especially vinylether derivatives has
attracted less attention.3–5 A few ligands have been
successfully employed for the reaction in the presence
of these substrates. The most popular ones are
triphenylphosphine, tri-ortho-tolylphosphine or 1,3-
bis(diphenylphosphino)propane. Even if the catalysts
formed by association of these ligands with palladium
complexes are quite efficient in terms of yield of adduct,
the efficiency in terms of ratio substrate/catalyst is quite
low. In general, fast decomposition of the catalysts
occurs, and 1–10% of these catalysts must be used. In
recent years, some more robust catalysts have been
tested with these substrates.2 For example, Herrmann,
Beller et al. have reported that the palladacycle [Pd(o-
tol)(OAc)]2 is very efficient for the reaction of 4-bro-
moacetophenone with styrene.3 A cyclopalladated imine
complex and an ortho-palladated phosphite complex
also led to high turnover numbers.4d,4e Recently, Fu et
al. described that the ligand P(t-Bu)3 is also an efficient
catalyst for the reaction of aryl chlorides with styrene
even at room temperature.4h The phosphine-free com-
plex PdCl2(SEt2)2 also led to high TONs even when the
reaction was performed in air.4i A few other ligands
also led to efficient catalysts.4 If mono- or diphosphine
ligands have been successfully used for this reaction, to
the best of our knowledge, the efficiency of tetra-
phosphine ligands has not been demonstrated.
The nature of phosphine ligands on complexes has an
important influence on the rate of catalysed reactions.
In order to obtain highly stable palladium catalysts, we
have prepared the new tetraphosphine ligand,6 cis,cis,
cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopen-
tane or tedicyp7a (Fig. 1) in which four diphenylphos-
phino groups are stereospecifically bound to the same
face of a cyclopentane ring. The presence of these four
phosphines close to the metal centre seems to increase
the coordination of the ligand to the metal and there-
fore increase the stability of the catalyst. We have
reported recently the first results obtained in allylic
substitution,7 for Suzuki cross-coupling8 and for Heck
reaction using tedicyp as the ligand.9 Herein, we wish to
report on the Heck reaction in the presence of aryl
halides and styrene or vinylether derivatives using tedi-
cyp as the ligand.
For this study, based on our previous results,9 DMF
was chosen as the solvent and potassium carbonate as
the base. The reactions were performed at 140°C in the
presence of a 1/2 ratio of [Pd(C3H5)Cl]2/tedicyp as
catalyst. First, we tried to evaluate the reactivity of
Ph2P
PPh2
Ph2P
PPh2
* Corresponding authors. Tel.: 00-33-4-91-28-84-16; fax: 00-33-4-91-
98-38-65 (H.D.); tel.: 00-33-4-91-28-88-25 (M.S.); e-mail:
henri.doucet@univ.u-3mrs.fr; m.santelli@univ.u-3mrs.fr
Tedicyp
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00219-8

2192
M. Feuerstein et al. / Tetrahedron Letters 43 (2002) 2191–2194
styrene and styrene derivatives (Scheme 1, Table 1).
Surprisingly, we observed no significant electronic effect
of the para-substituents on the aryl bromide on the rate
of the reaction. For example when a ratio substrate/cat-
alyst of 1 000 000 was used in the presence of the
deactivated bromoanisole or in the presence of the
activated 4-bromobenzophenone, conversions of 21 and
58% were obtained, respectively (entries 4 and 15). We
also obtained similar reaction rates with 4-fluorobro-
mobenzene, 4-nitrobromobenzene or 3,5-bistrifluoro-
methylbromobenzene (entries 8, 11 and 18). Moreover,
the reaction performed with iodobenzene or bromoben-
zene also led to similar reaction rates (entries 1 and 5).
On the other hand, in the presence of sterically hin-
dered aryl bromides, lower TONs were obtained
(entries 21 and 22). Next we studied the influence of the
substituents on styrene on the rate of the reaction.
Activated or deactivated styrene derivatives led to simi-
lar reaction rates (entries 23–27). In the presence of
ortho-substituted styrene derivatives, a significant steric
effect was observed. For example, the reaction using
9-vinylanthracene with 4-trifluoromethylbromobenzene
led to a TON of 325 (entry 28).
Several reactions were also performed in air9a and we
observed that in all cases the catalyst retains activity
(Table 1, entries 3, 7–9, 14–16 and 18). In air, TONs of
95 000 and 400 000 can be obtained with substrates
such as 4-bromo-N,N-dimethylaniline or 4-bromoben-
zophenone. In order to confirm the respective reaction
rates of styrene derivatives, we also performed competi-
tive reactions using an equimolar mixture of styrene
Scheme 1.
Table 1. Heck reaction with styrene derivatives catalysed by tedicyp–palladium complex (Scheme 1)10
Entry
Aryl halide
Styrene derivative
Ratio substrate/catalyst
Yield (%)a,c
1
2
3
4
5
6
7
8
Iodobenzene
Iodobenzene
4-Bromoanisole
4-Bromoanisole
Bromobenzene
Bromobenzene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
100 000
1 000 000
100 000
1 000 000
100 000
1 000 000
100 000
1 000 000
100 000
1 000 000
100 000
10 000
100 000
1 000 000
100 000
1 000 000
100 000
10 000
10 000
1000
1000
100 000
1 000 000
100 000
100 000
1 000 000
500
52b
11
82b (80)
21
87b
7
4-Fluorobromobenzene
4-Fluorobromobenzene
4-Bromo-N,N-dimethylaniline
4-Bromo-N,N-dimethylaniline
4-Nitrobromobenzene
4-Bromobenzophenone
4-Bromobenzophenone
4-Bromobenzophenone
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
3,5-Bistrifluoromethylbromobenzene
2-Bromoanisole
2-Bromofluorobenzene
9-Bromoanthracene
2,4,6-Triisopropylbromobenzene
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Bromoanisole
75b (99)
(54)
(95)b
28
9
10
11
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
30
31
32
33
75b
100d
92b (95)
58 (40)
95b (99)
14
Styrene
Styrene
Styrene
Styrene
66 (47)b
70b
89b
65b
Styrene
20b
3,5-Bistrifluoromethylstyrene
3,5-Bistrifluoromethylstyrene
4-Methoxystyrene
4-Methoxystyrene
4-Methoxystyrene
9-Vinylanthracene
2,4,6-Trimethylstyrene
2,4,6-Trimethylstyrene
4-Vinylpyridine
4-Vinylpyridine
88b
56
51b
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Bromobenzophenone
4-Bromobenzophenone
4-Bromobenzophenone
100
56
65b
1000
1000
1000
10 000
82
75b,e
100
68
Conditions: catalyst [Pd(C3H5)Cl]2/tedicyp 1/2 see: Ref. 7a, ArX (1 equiv.), styrene derivative (2 equiv.), K2CO3 (2 equiv.), DMF, 140°C, 24 h,
under argon, E isomer was obtained selectively in all cases (>95%).
a GC or NMR yields.
b Isolated yields.
c Yields in parentheses correspond to reactions performed in air.
d Reaction time: 1 h.
e Ratio of regioisomers E-1,2-diarylethene/1,1-diarylethene was 55/45.

M. Feuerstein et al. / Tetrahedron Letters 43 (2002) 2191–2194
2193
and styrene derivatives (Scheme 2). A minor electronic
effect and an important steric effect on the rate on the
reaction were confirmed.
bromoanisole a very low TON of 25 was obtained
(Table 2, entry 3; Scheme 3). On the other hand, with
activated aryl bromides such as 4-bromobenzaldehyde,
4-bromobenzophenone or 3,5-bistrifluoromethyl bro-
mobenzene TONs of 8500–42 000 were obtained
(entries 4–10). In the presence of iodobenzene a high
TON was also observed (entries 1 and 2). With ortho-
substituted arylbromides lower reaction rates were
observed (entries 11–15). In all cases mixtures of linear
and branched products were obtained. The regioselec-
Next, we tried to determine the efficiency of the Pd/
tedicyp catalyst in the presence of vinylether deriva-
tives. First, we studied the reaction in the presence of
n-butylvinylether. With this vinyl derivative, we
observed a very important electronic effect of the aryl
bromide on the rate of the reaction. With deactivated
R1
R1
[Pd(C3H5)Cl]2/tedicyp
Ratio S/C: 100 000
+
F3C
Br +
+
F3C
R2
DMF, K2CO3,
140°C, 20h
F3C
R2
R3
R3
a
b
10 mmol
20 mmol
20 mmol
R
R
1 = 3-CF3 , R2 = 5-CF3, R3 = H: conv. 100%, ratio a/b = 31/69
1 = 4-MeO, R2 = H, R3 = H: conv. 100%, ratio a/b = 50/50
R1 = 2-Me, R2 = 4-Me, R3 = 6-Me: conv. 60%, ratio a/b = 96/4
Scheme 2.
Scheme 3.
Table 2. Heck reaction with vinylether derivatives catalysed by tedicyp–palladium complex (Scheme 3).10
Entry
Aryl bromide
Vinylether
Ratio substrate/catalyst
Selectivity G/Z/E
Yield (%)
1
2
3
4
5
6
7
8
Iodobenzene
Iodobenzene
4-Bromoanisole
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
n-Butylvinylether
Cyclohexylvinylether
Cyclohexylvinylether 100 000
Cyclohexylvinylether 200
Cyclohexylvinylether 100 000
Cyclohexylvinylether 10 000
Cyclohexylvinylether 100 000
t-Butylvinylether
t-Butylvinylether
t-Butylvinylether
t-Butylvinylether
t-Butylvinylether
t-Butylvinylether
t-Butylvinylether
10 000
100 000
100
10 000
10 000
100 000
10 000
1000
10 000
10 000
1000
1000
1000
53/19/28
49/23/28
66/10/24
14/32/54
23/28/49
22/29/49
20/33/47
25/25/50
29/29/42
29/41/30
46/17/37
23/27/50
28/30/42
28/21/51
60/18/22
25/52/23
42/41/17
48/15/37
6/36/58
9/32/59
8/30/62
33/54/13
14/34/52
4/49/47
8/34/58
7/34/59
1/49/50
14/52/34
89
66a
25
4-Bromobenzaldehyde
4-Bromobenzophenone
4-Bromobenzophenone
4-Bromobenzonitrile
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
3,5-Bistrifluoromethylbromobenzene
2-Bromotoluene
2-Bromobenzaldehyde
2-Bromobenzonitrile
2-Trifluoromethylbromobenzene
9-Bromoanthracene
90
100a
42
88
99a
45
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
85
83
73
61
1000
1000
10 000
26
45
Iodobenzene
Iodobenzene
4-Bromoanisole
100a
58
68
4-Bromobenzophenone
4-Bromobenzaldehyde
4-Bromobenzaldehyde
Iodobenzene
4-Trifluoromethylbromobenzene
4-Bromobenzophenone
4-Bromobenzaldehyde
4-Bromobenzaldehyde
4-Bromoacetophenone
3,5-Bistrifluoromethylbromobenzene
60
100a
61
1000
1000
10 000
1000
10 000
1000
1000
78
90
52
100a
22
100a
88
Conditions: catalyst [Pd(C3H5)Cl]2/tedicyp 1/2, see: Ref. 7a, ArX (1 equiv.), vinylether (2 equiv.), K2CO3 (2 equiv.), DMF, 140°C, 24 h, under
argon, isolated yields.
a GC or NMR yields.

2194
M. Feuerstein et al. / Tetrahedron Letters 43 (2002) 2191–2194
8
tivity in favour of the linear isomer was higher in the
presence of activated aryl bromides. Finally, we per-
formed the reaction with the sterically demanding
ethers cyclohexylvinylether and t-butylvinylether. In all
cases we observed higher regioselectivities in favour of
the linear isomer. For example, for the reaction of
4-bromobenzophenone in the presence of cyclo-
hexylvinylether a ratio linear/branched isomers of 94/6
was observed (entry 19). In the presence of n-
butylvinylether the ratio was 78/22 (entry 6). With
cyclohexylvinylether quite high reaction rates were
observed. On the other hand, with t-butylvinylether
much lower TONs were obtained.
ladacycles, see: (a) Herrmann, W. A.; Brossmer, C.; Ofele,
K.; Reisinger, C.; Riermeier, T.; Beller, M.; Fisher, H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1844; (b) Littke,
A.; Fu, G. J. Org. Chem. 1999, 64, 10; (c) Miyazaki, F.;
Yamaguchi, K.; Shibasaki, M. Tetrahedron Lett. 1999, 40,
7379; (d) Gai, X.; Grigg, R.; Ramzan, I.; Sridharan, V.;
Collard, S.; Muir, J. Chem. Commun. 2000, 2053; (e)
Gibson, S.; Foster, D.; Eastham, D.; Tooze, R.; Cole-
Hamilton, D. Chem. Commun. 2001, 779.
3. Herrmann, W. A.; Brossmer, C.; Reisinger, C.; Riermeier,
8
T.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357.
4. For examples of Heck reaction using styrene: (a) Cabri,
W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem.
1992, 57, 3558; (b) Bumagin, N. A.; Bykov, V. V.;
Sukhomlinova, L. I.; Tolstaya, T. P.; Beletskaya, I. P. J.
Organomet. Chem. 1995, 486, 259; (c) Ohff, M.; Ohff, A.;
Boom, M.; Milstein, D. J. Am. Chem. Soc. 1997, 119,
11687; (d) Albisson, D.; Bedford, R.; Scully, P. N. Tetra-
hedron Lett. 1998, 39, 9793; (e) Ohff, M.; Ohff, A.;
Milstein, D. Chem. Commun. 1999, 357; (f) Bergbreiter,
D.; Osburn, P.; Liu, Y.-S. J. Am. Chem. Soc. 1999, 121,
9531; (g) Gruber, A.; Zim, D.; Ebeling, G.; Monteiro, A.;
Dupont, J. Org. Lett. 2000, 2, 1287, (h) Littke, A.; Fu, G.
J. Am. Chem. Soc. 2001, 123, 6989; (i) Gruber, A.;
Pozebon, D.; Monteiro, A.; Dupont, J. Tetrahedron Lett.
2001, 42, 7345; (j) Iyer, S.; Jayanthi, A. Tetrahedron Lett.
2001, 42, 7877.
5. For examples of Heck reaction using enol ethers: (a)
Hallberg, A.; Westfelt, L.; Holm, J. Org. Chem. 1981, 46,
5414; (b) Andersson, C.-M.; Hallberg, A.; Daves, D. J.
Org. Chem. 1987, 52, 3529; (c) Cabri, W.; Candiani, I.;
Bedeschi, A.; Santi, R.; Tetrahedron Lett. 1991, 32, 1753;
(d) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S. J. Org.
Chem. 1992, 57, 1481; (e) Larhed, M.; Andersson, C.,
Hallberg, A. Acta Chem. Scand. 1993, 47, 212; (f) Cabri,
W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem.
1993, 58, 7421; (g) Cabri, W.; Candiani, I. Acc. Chem.
Res. 1995, 28, 2; (h) Vallin, K.; Larhed, M.; Hallberg, A.
J. Org. Chem. 2001, 66, 4340.
In conclusion, the use of the tetradentate ligand Tedi-
cyp associated with a palladium complex provides a
convenient catalyst for the Heck reaction with styrene
and vinylether derivatives. This catalyst seems to be
much more efficient than the complexes formed with
triphenylphosphine ligand. This efficiency probably
comes from the presence of the four diphenylphosphi-
noalkyl groups stereospecifically bound to the same
face of the cyclopentane ring which probably increases
the coordination of the ligand to the metal and prevent
precipitation of the catalyst. In the presence of this
catalyst the Heck vinylation of aryl bromides with
styrene derivatives can be performed with as little as
0.001 mol% catalyst. These results represent an envi-
ronmentally friendly procedure. Moreover, due to the
high price of palladium, the practical advantage of such
low catalyst loading reactions can become increasingly
important for industrial processes.
Acknowledgements
We thank the CNRS for providing financial support
and M.F. is grateful to the Ministe`re de la Recherche et
de la Technologie for a grant.
6. For a review on the synthesis of polypodal diphenylphos-
phine ligands, see: Laurenti, D.; Santelli, M. Org. Prep.
Proc. Int. 1999, 31, 245–294.
7. (a) Laurenti, D.; Feuerstein, M.; Pe`pe, G.; Doucet, H.;
Santelli, M. J. Org. Chem. 2001, 66, 1633; (b) Feuerstein,
M.; Laurenti, D.; Doucet, H.; Santelli, M. Chem. Com-
mun. 2001, 43.
References
1. For reviews on the palladium-catalysed Heck reaction,
see: (a) Heck, R. F. Palladium Reagents in Organic Syn-
theses; Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W.,
Eds.; Academic Press: London, 1985; p. 2; (b) Heck, R. F.
In Comprehensive Organic Synthesis; Trost, B. M.; Flem-
ing, I.; Eds. Vinyl Substitution with Organopalladium
Intermediates; Pergamon: Oxford, 1991; Vol. 4; (c)
Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of
Palladium-Catalysed Organic Reactions; Academic Press:
London, 1997; (d) Reetz, M. T. In Transition Metal
Catalysed Reactions; Davies, S. G.; Murahashi, S.-I.,
Eds.; Blackwell: Oxford, 1999; (e) Beletskaya, I.; Chep-
rakov, A. Chem. Rev. 2000, 100, 3009; (f) Withcombe, N.;
Hii (Mimi) K. K.; Gibson, S. Tetrahedron, 2001, 57, 7449.
2. For recent examples of Heck reactions catalysed by pal-
8. Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucet, H.;
Santelli, M. Chem. Commun. 2001, 325.
9. (a) Feuerstein, M.; Doucet, H.; Santelli, M. J. Org. Chem.
2001, 66, 5923; (b) Feuerstein, M.; Doucet, H.; Santelli,
M. Synlett 2001, 1980.
10. As a typical experiment, the reaction of 4-bromoben-
zophenone (2.61 g, 10 mmol), styrene (2.08 g, 20 mmol)
and K2CO3 (2.76 g, 20 mmol) at 140°C during 20 h in dry
DMF (10 mL) in the presence of cis,cis,cis-1,2,3,4-
tetrakis (diphenylphosphinomethyl)cyclopentane/[PdCl-
(C3H5)]2 complex (0.0001 mmol) under argon affords the
corresponding product after evaporation and filtration on
silica gel in 92% (2.61 g) isolated yield.