Tetraphosphine/palladium-catalyzed Heck reactions of aryl halides with disubstituted alkenes

Article abstract of DOI:10.1016/j.tetlet.2003.09.092

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/ [PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of disubstituted alkenes such as methyl crotonate, ethyl cinnamate, methyl methacrylate or α-methylstyrene with a variety of aryl halides. In the presence of 1,2-disubstituted alkenes the stereoselectivities of the reactions strongly depend on the substituents of the alkenes. Selectivities up to 97% in favor of E-isomers can be obtained for the addition to methyl crotonate. With the 1,1-disubstituted alkenes methyl methacrylate or α-methylstyrene mixtures of products are obtained.

Full text of DOI:10.1016/j.tetlet.2003.09.092

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8487–8491
Tetraphosphine/palladium-catalyzed Heck reactions of aryl
halides with disubstituted alkenes
Isabelle Kondolff, 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 16 July 2003; revised 2 September 2003; accepted 12 September 2003
Abstract—cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C3H5)]2 efficiently catalyses the Heck reaction
of disubstituted alkenes such as methyl crotonate, ethyl cinnamate, methyl methacrylate or a-methylstyrene with a variety of aryl
halides. In the presence of 1,2-disubstituted alkenes the stereoselectivities of the reactions strongly depend on the substituents of
the alkenes. Selectivities up to 97% in favor of E-isomers can be obtained for the addition to methyl crotonate. With the
1,1-disubstituted alkenes methyl methacrylate or a-methylstyrene mixtures of products are obtained.
© 2003 Elsevier Ltd. All rights reserved.
The palladium-catalyzed Heck vinylation reaction is
one of the most powerful methods for the formation of
CꢀC bonds.1 The efficiency of several catalysts for the
reaction of aryl halides with acrylates or styrene deriva-
tives has been studied in detail. On the other hand, the
reaction in the presence of disubstituted alkenes such as
ethyl cinnamate or a-methylstyrene has attracted less
attention.2–4 A few ligands have been successfully
employed for the reaction in the presence of disubsti-
tuted alkenes. The most popular one is triphenylphos-
phine, but the palladium complexes formed with this
ligand are generally not very efficient in terms of sub-
strate/catalyst ratio. In recent years, more efficient cata-
lysts such as palladacycles have been tested with these
substrates.5 For example, Beller et al. reported that a
phosphapalladacycle is very efficient for the reactions
with 1,1-disubstituted olefins.4b In the monophosphine
ligand series, good results have been reported recently
by Fu et al. They reported that the ligand P(t-Bu)3 is an
efficient catalyst for the reaction of 4-dimethylamino-
bromobenzene with methyl methacrylate even at room
temperature.2h,4d If monophosphine ligands or pallada-
cycles have been successfully used for the reaction with
these alkenes, to the best of our knowledge, the
efficiency of tetraphosphine ligands has not been
demonstrated.
In order to obtain stable and efficient palladium cata-
lysts, we have prepared the new tetraphosphine ligand,
cis,cis,cis - 1,2,3,4 - tetrakis(diphenylphosphinomethyl)
cyclopentane or tedicyp6 (Fig. 1) in which four
diphenylphosphino groups are stereospecifically bound
to the same face of a cyclopentane ring. We have
already reported the results obtained in allylic substitu-
tions,6 for Suzuki cross-couplings,7 for Heck reactions8
and for Sonogashira alkynylations9 using tedicyp as the
ligand. In order to further establish the requirements
for a successful Heck reaction with our catalyst, we
herein report on the reaction of aryl halides with disub-
stituted alkenes.
For this study, based on previous results,8 DMF was
chosen as the solvent and K2CO3 as the base. The
reactions were performed at 130°C under argon in the
presence of a 1:2 ratio of [Pd(C3H5)Cl]2/tedicyp as
catalyst.
We first studied the reactivity of 1,2-disubstituted alke-
nes with several aryl halides in the presence of 1–0.01
mol% catalyst (Scheme 1, Table 1). In all cases, mix-
tures of isomers were obtained, however, the selectivity
Keywords: palladium; tetraphosphine; Heck reaction; disubstituted
alkene.
* Corresponding authors. Tel.: +33-4-91-28-84-16; fax: +33-4-91-98-
38-65 (H.D.); Tel.: +33-4-91-28-88-25 (M.S.); e-mail: henri.doucet@
univ.u-3mrs.fr; m.santelli@univ.u-3mrs.fr
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.092

8488
I. Kondolff et al. / Tetrahedron Letters 44 (2003) 8487–8491
Scheme 1.
Table 1. Heck reactions with 1,2-disubstituted alkenes catalyzed by the tedicyp-palladium complex (Scheme 1)10
Entry
Aryl halide
Alkene
Ratio
substrate/catalyst
Selectivity for isomers
Yield (%)b
E/Z/G (%) (Scheme 1)a
1
2
3
4
5
6
7
8
Iodobenzene
Iodobenzene
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
Methyl crotonate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Ethyl cinnamate
E-Benzalacetone
E-Benzalacetone
E-Benzalacetone
E-Benzalacetone
E-Benzalacetophenone
E-Benzalacetophenone
E-Benzalacetophenone
Diethyl maleate
1000
10,000
1000
250
1000
1000
1000
1000
250
88/6/6
E>95
E>97
86/8/6
E>95
E>97
E>95
E>95
E>97
–
91 (100)
(60)
60
89 (100)
88 (100)
82
81
81
87
(100)
82
(25)
88
90
91
93
(46)
81
80
4-Bromoacetophenone
4-Bromobenzophenone
4-Fluorobromobenzene
4-Dimethylaminobromobenzene
4-Bromoanisole
4-tButylbromobenzene
3-Bromopyridine
Iodobenzene
Bromobenzene
Bromobenzene
3-Trifluoromethylbromobenzene
4-Bromotoluene
4-Dimethylaminobromobenzene
4-Bromoanisole
4-Bromoanisole
2,4,6-Trimethylbromobenzene
Iodobenzene
Bromobenzene
4-Methylbromobenzene
4-Bromoanisole
Iodobenzene
4-Methylbromobenzene
4-Bromoanisole
Iodobenzene
Iodobenzene
Iodobenzene
4-Bromoanisole
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
1000
250
–
–
1000
1000
1000
1000
250
1000
100
250
100
250
100
1000
250
67/33/–c
84/16/–
74/26/–
79/21/–
82/18/–
62/38/–
–
–
90
72
53/47/–c
54/46/–c
–
83 (100)
85 (100)
89 (100)
81 (97)
92 (100)
(100)
81 (100)
75
50/50/–
50/50/–
30/70d
39/61d
17/83d
38/20/42e
100
250
1000
50
25
Diethyl maleate
Diethyl fumarate
E-Anethole
Conditions: catalyst [Pd(C3H5)Cl]2/tedicyp 1:2 see Ref. 6, ArX (1 equiv.), alkene (2 equiv.), K2CO3 (2 equiv.), DMF, 20 h, 130°C, under argon,
isolated yields (mixture of isomers), ratio substrate/catalyst based on the aryl halide.
a Selectivities determined by GC and NMR.
b Yields in parentheses correspond to GC or NMR yields.
c Stereochemistry of the isomers was not determined.
d Ratio diethyl phenylfumarate: diethyl phenylmaleate.
e Ratio E-1,2-bis(4-methoxyphenyl)prop-1-ene: 2,3-bis(4-methoxyphenyl)prop-1-ene:1,1-bis(4-methoxyphenyl)prop-1-ene.
strongly depended on the substituents of the alkenes. In
the presence of methyl crotonate high selectivities in
favor of the E-isomer were obtained (up to 97%) (Table
1, entries 1–9). A minor influence of the electronic factors
of the aryl halide on the reaction rate was observed.
Similar turn over numbers (TONs) were observed using
activated 4-bromoacetophenone and deactivated 4-bro-
moanisole: 600 and 810 (Table 1, entries 3 and 7)
indicating that, as expected, the rate-limiting step of the
reaction with this sterically hindered alkene is not the
oxidative addition of the aryl halide. Similar reaction
rates were obtained for the addition of aryl halides to
ethyl cinnamate but lower selectivities in favor of the
E-isomer were observed (62–84%) (Table 1, entries
10–18). Almost equimolar mixtures of E- and Z-isomers
were obtained for the addition to benzalacetone and
benzalacetophenone (Table 1, entries 19–25). The
observed lack of stereoselectivity of these reactions might
be due to equilibration of the products subsequent to the
Heck reaction by base-catalyzed isomerization.2e

I. Kondolff et al. / Tetrahedron Letters 44 (2003) 8487–8491
8489
the E-isomer was obtained in 35–93% selectivity (Table
2, entries 1–17). The formation of large amounts of
G-isomers and traces of Z-isomers were also observed
in some cases. The highest selectivities were obtained in
the presence of electron-poor aryl bromides. For exam-
ple a selectivity of 93% in favor of the E-isomer was
obtained for the reaction with 4-bromobenzonitrile
(Table 2, entry 3). On the other hand, with the electron-
rich aryl bromide, 4-bromoanisole, a lower selectivity of
57% in favor of the E-isomer was obtained (Table 2,
entry 8). Even the di-ortho-substituted aryl bromide
2,4,6-trimethylbromobenzene was efficiently converted
into the adducts. However, in this case a greater quan-
tity of catalyst was required, and the formation of 65%
of the G-isomer was observed (Table 2, entry 14).
Presumably, the steric demand of the two ortho methyl
The reaction of diethyl maleate with iodobenzene in the
presence of 0.1 mol% catalyst led to mixtures of diethyl
2-phenylfumarate and diethyl 2-phenylmaleate (Table
1, entries 26 and 27). A similar selectivity but a much
lower reactivity was observed with diethyl fumarate
(Table 1, entry 28). The reactivity of E-anethol was also
studied (Table 1, entry 29). With this substrate a mix-
ture of three regio- and stereoisomers was obtained. In
summary, many of these 1,2-disubstituted alkenes can
be reacted in the presence of low catalyst loadings and
the selectivity strongly depends on the substituents of
the alkene.
We next studied the reactivity of two 1,1-disubstituted
alkenes (Scheme 2, Table 2). In all cases, mixtures of
three isomers were obtained. With methyl methacrylate,
Scheme 2.
Table 2. Heck reactions with 1,1-disubstituted alkenes catalyzed by tedicyp-palladium complex (Scheme 2)10
Entry
Aryl halide
Alkene
Ratio
substrate/catalyst
Selectivity for isomers
Yield (%)b
E/Z/G (%) (Scheme 2)a
1
2
3
4
5
6
7
8
Iodobenzene
Iodobenzene
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
Methyl methacrylate
a-Methylstyrene
10,000
100,000
1000
1000
1000
100
1000
1000
1000
100
100
250
100
50
250
250
1000
250
1000
10,000
250
1000
10,000
1000
250
1000
250
62/0/38
62/0/38
93/0/7
94
(15)
4-Bromobenzonitrile
4-Trifluoromethylbromobenzene
4-Bromobenzophenone
4-Dimethylaminobromobenzene
4-Fluorobromobenzene
4-Bromoanisole
82 (100)
88 (100)
81 (100)
55
91 (100)
90
87 (100)
50 (57)
84
78 (100)
80 (100)
83 (100)
83 (100)
87 (100)
95
(100)
62 (70)
(28)
(100)
87 (97)
(30)
76
80 (99)
(51)
70/12/18
75/10/15
68/6/26
56/0/44
57/4/39
57/5/38
70/6/24
50/2/48
66/6/28
58/4/38
35/0/65
49/2/49
77/6/17
48/16/36
62/12/26
54/11/35
38/7/55
46/6/48
42/4/54
37/5/58
52/6/42
46/7/47
44/8/48
78/13/9
72/14/14
50/5/45
50/5/45
18/0/82
9
4-tButylbromobenzene
2-Bromobenzonitrile
2-Fluorobromobenzene
2-Methylbromobenzene
2-Methoxybromobenzene
2,4,6-Trimethylbromobenzene
3-Bromopyridine
3-Bromoquinoline
2-Bromothiophene
Iodobenzene
Iodobenzene
Iodobenzene
Bromobenzene
Bromobenzene
Bromobenzene
4-Dimethylaminobromobenzene
4-Bromoanisole
4-Bromoanisole
4-Bromoacetophenone
4-Bromoacetophenone
2-Methylbromobenzene
2-Methylbromobenzene
2,4,6-Trimethylbromobenzene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
(100)
82
95
(86)
65
a-Methylstyrene
1000
250
1000
250
a-Methylstyrene
a-Methylstyrene
a-Methylstyrene
Conditions: catalyst [Pd(C3H5)Cl]2/tedicyp 1:2 see Ref. 6, ArX (1 equiv.), alkene (2 equiv.), K2CO3 (2 equiv.), DMF, 20 h, 130°C, under argon,
isolated yields (mixture of isomers), ratio substrate/catalyst based on the aryl halide.
a Selectivities determined by GC and NMR.
b Yields in parentheses correspond to GC or NMR yields.

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I. Kondolff et al. / Tetrahedron Letters 44 (2003) 8487–8491
groups disfavors one of the two possible b-hydride
eliminations to generate mainly the olefin G.2h
Trost, B. M.; Fleming, I., Eds. Vinyl Substitution with
Organopalladium Intermediates; Pergamon: Oxford, 1991;
Vol. 4; (b) de Meijere, A.; Meyer, F. Angew. Chem., Int.
Ed. 1994, 33, 2379; (c) Malleron, J.-L.; Fiaud, J.-C.;
Legros, J.-Y. Handbook of Palladium-Catalyzed Organic
Reactions; Academic Press: London, 1997; (d) Reetz, M.
T. Transition Metal Catalyzed Reactions; Davies, S. G.;
Murahashi, S.-I., Eds.; Blackwell Science: Oxford, 1999;
(e) Beletskaya, I.; Cheprakov, A. Chem. Rev. 2000, 100,
3009; (f) Withcombe, N.; Hii (Mimi) K. K.; Gibson, S.
Tetrahedron 2001, 57, 7449; (g) Littke, A.; Fu, G. Angew.
Chem., Int. Ed. 2002, 41, 4176.
Heteroaromatic substrates such as 3-bromopyridine,
3-bromoquinoline or 2-bromothiophene in the presence
of methyl methacrylate also led to the expected mixture
of adducts (Table 2, entries 15–17).
Selectivities similar to those obtained with methyl
methacrylate were observed for the addition of aryl
halides to a-methylstyrene (Table 2, entries 18–31). The
E-isomer was obtained in 18–78% selectivity. Higher
selectivities in favor of the E-isomer were observed in
the presence of electron-poor aryl bromides than with
electron-rich aryl bromides. The sterically congested
2,4,6-trimethylbromobenzene also led mainly to the
G-isomer (Table 2, entry 31). With this alkene the
oxidative addition of the palladium(0) is apparently not
the rate-limiting step of the reaction. For example,
TONs of 2800 and 3000 were obtained for the addition
of iodobenzene and bromobenzene to a-methylstyrene
(Table 2, entries 18–23).
2. For examples of Heck reactions with alkyl cinnamates or
crotonates, see: (a) Melpolder, J.; Heck, R. J. Org. Chem.
1976, 41, 265; (b) Cortese N.; Ziegler, C.; Hrnjez, B.,
Heck, R. J. Org. Chem. 1978, 43, 2952; (c) Busacca, C.;
Johnson, R. Tetrahedron Lett. 1992, 33, 165; (d) Moreno-
Man˜as, M.; Pe´rez, M.; Roser, P. Tetrahedron Lett. 1996,
37, 7449; (e) Gu¨rtler, C.; Buchwald, S. Chem. Eur. J.
1999, 5, 3107; (f) Ohff, M.; Ohff, A.; Milstein D. Chem.
Commun. 1999, 357; (g) Blettner, C.; Ko¨nig, W.; Stenzel,
W.; Schotten, T. Tetrahedron Lett. 1999, 40, 2101; (h)
Littke, A.; Fu, G. J. Am. Chem. Soc. 2001, 123, 6989; (i)
Calo, V.; Nacci, A.; Monopoli, A.; Lopez, L.; di Cosmo,
A. Tetrahedron 2001, 57, 6071.
3. For examples of Heck reactions with E-benzalacetone or
E-benzalacetophenone, see: (a) Cacchi, S.; Arcadi, A. J.
Org. Chem. 1983, 48, 4236; (b) Amorese, A.; Arcadi, A.;
Bernocchi, E.; Cacchi, S.; Cerrini, S.; Fereli, W.; Ortar,
G. Tetrahedron 1989, 45, 813.
4. For examples of Heck reactions with methyl methacrylate
or a-methylstyrene, see: (a) Beller, M.; Riermeier, T.
Tetrahedron Lett. 1996, 37, 6535; (b) Beller, M.; Rier-
meier T. Eur. J. Inorg. Chem. 1998, 1, 29; (c) Bo¨hm, V.;
Herrmann, W. Chem. Eur. J. 2000, 6, 1017; (d) Nether-
ton, M.; Fu, G. Org. Lett. 2001, 3, 4295; (e) Albeniz, A.;
Espinet, P.; Martin-Ruiz, B.; Milstein, D. J. Am. Chem.
Soc. 2001, 123, 11504; (f) Chandrasekhar, V.; Athi-
moolam, A. Org. Lett. 2002, 4, 2113 and Refs. 2e, 2h.
5. For recent examples of Heck reactions catalyzed by
palladacycles, see: (a) Herrmann, W. A.; Brossmer, C.;
In summary, in the presence of the tedicyp/palladium
complex, the Heck vinylation of several aryl halides
with 1,1- and 1,2-disubstituted alkenes can be per-
formed with as little as 0.01 mol% catalyst. In general,
mixtures of isomers were obtained. The selectivity of
the reactions depends on the substituents of the alke-
nes. Addition to methyl crotonate is highly selective in
favor of the E-isomer. Addition to E-benzalacetophe-
none led to almost equimolar mixtures of E- and
Z-isomers. For the addition to methyl methacrylate, in
general the major isomer was the E-isomer. The behav-
ior of all these reactions depends on the electronic and
steric factors of the aryl halides and of the alkenes.
These observations suggest that the product distribu-
tion in some cases not only comes from the conforma-
tion of the Pd-substrate intermediates but also from
thermodynamic stability and base-catalyzed isomeriza-
tion of the products. In general the rate-limiting step of
these reactions does not seem to be the oxidative addi-
tion of the aryl halides. For this reason, this method is
applicable to the coupling of both electron-deficient
and electron-rich aryl bromides. Both in terms of sub-
strate/catalyst ratio and reaction scope, this catalyst is
effective for Heck reactions of disubstituted alkenes.
Due to the high price of palladium, the advantage of
such low catalyst loading reactions could become
increasingly important for industrial processes.
8
Ofele, K.; Reisinger, C.; Riermeier, T.; Beller, M.; Fisher,
H. Angew. Chem., Int. Ed. 1995, 34, 1844; (b) Ohff, M.;
Ohff, A.; Boom, M.; Milstein, D. J. Am. Chem. Soc.
1997, 119, 11687; (c) Albisson, D.; Bedford, R.; Scully, P.
N. Tetrahedron Lett. 1998, 39, 9793; (d) Ohff, M.; Ohff,
A.; Milstein, D. Chem. Commun. 1999, 357; (e) Miyazaki,
F.; Yamaguchi, K.; Shibasaki, M. Tetrahedron Lett.
1999, 40, 7379; (f) Bergbreiter, D.; Osburn, P.; Liu, Y.-S.
J. Am. Chem. Soc. 1999, 121, 9531; (g) Gai, X.; Grigg,
R.; Ramzan, I.; Sridharan, V.; Collard, S.; Muir, J.
Chem. Commun. 2000, 2053; (h) Gibson, S.; Foster, D.;
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mun. 2001, 779.
Acknowledgements
6. Laurenti, D.; Feuerstein, M.; Pe`pe, G.; Doucet, H.; San-
We thank the CNRS and the ‘Conseil Ge´ne´ral des
Bouches-du-Rhoˆne, Fr’ for providing financial support.
telli, M. J. Org. Chem. 2001, 66, 1633.
7. Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucet, H.;
Santelli, M. Chem. Commun. 2001, 325.
8. (a) Feuerstein, M.; Doucet, H.; Santelli, M. J. Org.
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(d) Berthiol, F.; Feuerstein, M.; Doucet, H.; Santelli, M.
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I. Kondolff et al. / Tetrahedron Letters 44 (2003) 8487–8491
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10. As a typical experiment (Table 1, entry 5), the reaction of
4-fluorobromobenzene (1.75 g, 10 mmol), methyl croto-
nate (2.00 g, 20 mmol) and K2CO3 (2.76 g, 20 mmol) at
130°C over 20 h in dry DMF (10 mL) in the presence of
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclo-
pentane/[PdCl(C3H5)]2 complex (0.01 mmol) under argon
afforded the corresponding (E)-product after evaporation
and filtration on silica gel (ether/pentane: 1/2) in 88%
(1.70 g) isolated yield. 1H NMR (300 MHz, CDCl3) l:
7.44 (dd, 2H, J=5.3 and 8.3 Hz), 7.04 (t, 2H, J=8.3 Hz),
6.08 (s, 1H), 3.74 (s, 3H), 2.53 (s, 3H).