Heck reaction with heteroaryl halides in the presence of a palladium-tetraphosphine catalyst

Article abstract of DOI:10.1016/S0040-4039(02)01109-7

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/1/2[PdCl (C₃H₅)]₂ system catalyses efficiently the Heck reaction of heteroaryl halides with n-butyl acrylate, styrene, vinylpyridine and vinyl ether derivatives. High turnover numbers can be obtained for the reactions with halo pyridines, quinolines, furans or thiophenes.

Full text of DOI:10.1016/S0040-4039(02)01109-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5625–5628
Heck reaction with heteroaryl halides in the presence of a
palladium–tetraphosphine catalyst
Florian Berthiol, 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 2 April 2002; accepted 10 June 2002
Abstract—cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/12[PdCl(C3H5)]2 system catalyses efficiently the Heck
reaction of heteroaryl halides with n-butyl acrylate, styrene, vinylpyridine and vinyl ether derivatives. High turnover numbers can
be obtained for the reactions with halo pyridines, quinolines, furans or thiophenes. © 2002 Elsevier Science Ltd. All rights
reserved.
Heteroaryl compounds have important biological prop-
erties. The palladium-catalysed Heck reaction between
heteroaryl halides and alkenes provides a very efficient
method for the preparation of several heteroaryl deriva-
tives.1 A few ligands have been successfully used for the
reaction in the presence of these substrates.2,3 The most
popular ones are triphenylphosphine or tri-ortho-
tolylphosphine. Even if the catalysts formed by associa-
tion 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 most
cases, fast decomposition of the catalysts occurs, and
1–10% of these catalysts must be used. For a few years,
some very efficient catalyst have been described for
Heck reaction.4 For example, Herrmann, Beller et al.
have reported that the palladacycle [Pd(o-tol)(OAc)]2 is
very efficient for the reaction of arylhalides with n-butyl
acrylate or styrene.5 The efficiency of such palladacycles
for the reaction with several aryl halides has been
studied in detail. However, the reaction with heteroaryl
halides in the presence of these stable catalysts has
attracted less attention, and to the best of our knowl-
edge, the efficiency of tetraphosphine ligands has not
been demonstrated.
cyclopentane or tedicyp7a (Fig. 1) in which four
diphenylphosphino 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
therefore increases the stability of the catalyst. We have
reported recently the first results obtained in allylic
substitution,7 for Suzuki cross-coupling8 and for Heck
reaction9 using tedicyp as the ligand. Herein, we wish to
report on the Heck reaction with heteroaryl halides and
acrylate, styrene, vinylpyridine or vinyl ether derivatives
in the presence of tedicyp 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 generally performed at
140°C under argon in the presence of a ratio 1/2 of
[Pd(C3H5)Cl]2/tedicyp as catalyst.
First, we studied the influence of the position of the
bromo substituent on pyridines on the rate of the
reaction with n-butyl acrylate (Scheme 1, Table 1). Due
to the electronegativity of the nitrogen atom, the a and
g positions of halo pyridines should be the most suscep-
tible to the oxidative addition to Pd(0).1 In fact, we
observed higher reaction rates for the coupling with the
b and g-substituted bromopyridines. For the reactions
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)-
Ph2P
PPh2
Ph2P
PPh2
Tedicyp
* 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
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01109-7

5626
F. Berthiol et al. / Tetrahedron Letters 43 (2002) 5625–5628
Ar
1/2 [Pd(C3H5)Cl]2 / tedicyp
R
Ar
R
Ar
+
Ar
X
+
+
DMF, K2CO3, 140°C
R
R
Ar = pyridine, quinoline, thiophene, furan
X = Br, I
Z
E
G
R = Ph, CO2-nBu, O-nBu, O-tBu, O-cyclohexyl, pyridine
Scheme 1.
A bromofuran: 5-bromo-2-furaldehyde with n-butyl
acrylate or styrene also led to the addition products.
However, these products are not thermally stable and
the reactions have to be performed at a lower temper-
ature (entries 48 and 49).
with n-butyl acrylate, TONs of 96 000 and 42 000 were
obtained, respectively (entries 8 and 15). With the a-
substituted bromopyridine a low TON of 50 was
observed (entry 1). With this substrate, the formation
of 2,2%-bipyridine was also observed.10 The formation
of this side product, which can act as a poison for
palladium catalysts, might be the reason of the low
reactivity of 2-bromopyridine. In the presence of sty-
rene a similar tendency was observed: 3- and 4-bro-
With these heteroaryl halides, several reactions were
also performed in the presence of vinyl ethers. Pyridi-
nes and quinolines are p-electron deficient heterocy-
cles. The regioselectivity of the addition to p-electron
deficient heterocycles should be in favour of the linear
isomers Z and E (Scheme 1). Thiophenes are p-elec-
tron excessive.1 With these heterocycles, the regioselec-
tivity of the reaction should be in favour of the
branched isomer G (Scheme 1). We observed in all
cases the formation of mixtures of linear and branched
products. As expected, in the presence of halo pyridi-
nes and quinolines the regioselectivity is generally in
favour of the linear isomers. They can be obtained in
59–74% selectivity (entries 12, 18, 24, 25 and 30). With
thiophenes, the regioselectivity in favour of the
branched isomer is very high. This regioisomer is
obtained in 89–95% selectivity when 2-halothiophenes
are used (entries 34, 39 and 40) and in 95% selectivity
with 3-bromothiophene (entry 45).
mopyridines
are
much
more
reactive
than
2-bromopyridine (entries 2, 9, 10, 16 and 17). With
styrene and 3-bromopyridine the reaction can be per-
formed with as little as 0.001% catalyst. Then, we
studied the influence of halogen on the reaction. In the
presence of 3-iodopyridine similar reaction rates to
with 3-bromopyridine are observed (entries 3–7). This
result seems to indicate that the oxidative addition of
these 3-halopyridines to palladium is not the rate-lim-
iting step of the reaction. A double Heck reaction has
also been performed successfully with 3,5-dibromopy-
ridine. This substrate with n-butyl acrylate or styrene
in the presence of 0.1–0.2% catalyst led selectively to
the diaddition products (entries 19 and 20).
Next, we studied the reactivity of bromoquinolines,
and we observed that their reactivity is similar to
pyridines. 3-Bromoquinoline in the presence of n-butyl
acrylate or styrene led the addition products in
960 000 and 61 000 TONs, respectively (entries 21 and
22). In the presence of the sterically hindered 4-bro-
moisoquinoline, lower TONs were obtained: 5000 and
4300 (entries 26–29).
Finally, a few reactions with the heteroalkenes 2- and
4-vinylpyridines have been performed. The reaction of
iodobenzene with 2-vinylpyridine is very slow (entries
50 and 51). Much higher reaction rates are observed in
the presence of 4-vinylpyridine (entries 52–54). With
this substrate and 3-bromopyridine or 2-bromothio-
phene, the synthesis of heterobiaryl adducts was also
performed in good yields (entries 13 and 41).
Then, we tried to determine the efficiency of the Pd/
tedicyp catalyst in the presence of halo thiophenes.
First, we studied the reaction with 2-iodo- and 2-bro-
mothiophenes. The reaction rates with these two sub-
strates in the presence of styrene are quite similar,
indicating that the oxidative addition to palladium of
these 2-halo thiophenes is probably not the rate-limit-
ing step of the reaction (entries 33 and 38). However,
in the presence of n-butyl acrylate, we observed higher
reaction rates with 2-iodothiophene than with 2-bro-
mothiophene (entries 31, 32, 35 and 36). We also
studied the influence of the position of the halogen on
thiophenes and we observed that with 3-bromothio-
phene, slightly lower TONs were obtained: 500–3400
(entries 42–44). The b,b%-disubstituted 3,4-dibromoth-
iophene is not very reactive. The diaddition product
using n-butyl acrylate can be obtained, however the
reaction requires 4% catalyst (entry 46). In the pres-
ence of 0.4% catalyst the mono addition product can
be obtained quite selectively (entry 47).
In conclusion, the use of the tetradentate ligand tedi-
cyp associated to a palladium complex provides a con-
venient catalyst for the Heck reaction with several
heteroaryl compounds. 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 prevent precipita-
tion of the catalyst. In the presence of this catalyst,
the Heck vinylation of heteroaryl halides such as 3-
bromopyridine or 3-bromoquinoline with n-butyl acryl-
ate, styrene or vinyl ether derivatives can be per-
formed with as little as 0.1–0.0001% catalyst. These
results represent an environmentally friendly proce-
dure. Moreover, due to the high price of palladium,
the practical advantage of such low catalyst loading
reactions can become increasingly important for indus-
trial processes.

F. Berthiol et al. / Tetrahedron Letters 43 (2002) 5625–5628
Table 1. Heck reaction catalysed by tedicyp–palladium complex11
5627
Entry
Aryl halide
Alkene
Ratio substrate/catalyst
Yield (%)a
1
2
3
4
5
6
7
8
9
2-Bromopyridine
2-Bromopyridine
3-Iodopyridine
3-Iodopyridine
3-Iodopyridine
n-Butyl acrylate
Styrene
n-Butyl acrylate
n-Butyl acrylate
Styrene
n-Butyl vinyl ether
Cyclohexyl vinyl ether
n-Butyl acrylate
Styrene
100
100
50b
40b
10 000
100 000
10 000
10 000
1000
100 000
10 000
100 000
10 000
1000
100c
55
43
3-Iodopyridine
3-Iodopyridine
88 (54/25/21)
68 (60/7/33)
3-Bromopyridine
3-Bromopyridine
3-Bromopyridine
3-Bromopyridine
3-Bromopyridine
3-Bromopyridine
4-Bromopyridinee
4-Bromopyridinee
4-Bromopyridinee
4-Bromopyridinee
4-Bromopyridinee
3,5-Dibromopyridine
3,5-Dibromopyridine
3-Bromoquinoline
3-Bromoquinoline
3-Bromoquinoline
3-Bromoquinoline
3-Bromoquinoline
4-Bromoisoquinoline
4-Bromoisoquinoline
4-Bromoisoquinoline
4-Bromoisoquinoline
4-Bromoisoquinoline
2-Iodothiophene
2-Iodothiophene
2-Iodothiophene
2-Iodothiophene
2-Bromothiophene
2-Bromothiophene
2-Bromothiophene
2-Bromothiophene
2-Bromothiophene
2-Bromothiophene
2-Bromothiophene
3-Bromothiophene
3-Bromothiophene
3-Bromothiophene
3-Bromothiophene
3,4-Dibromothiophene
3,4-Dibromothiophene
5-Bromo-2-furaldehyde
5-Bromo-2-furaldehyde
Iodobenzene
96d
89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Styrene
42c
n-Butyl vinyl ether
Cyclohexyl vinyl ether
4-Vinylpyridine
n-Butyl acrylate
n-Butyl acrylate
Styrene
75 (54/24/22)
87 (41/29/30)
84
1000
10 000
100 000
1000
10 000
1000
1000
500
1 000 000
100 000
10 000
1000
1000
1000
10 000
1000
10 000
1000
10 000
100 000
10 000
1000
1000
10 000
1000
10 000
1000
100
1000
1000
10 000
1000
250
25
250
1000
1000
100
1000
10 000
100 000
10 000
82
42c
90
Styrene
98c
n-Butyl vinyl ether
n-Butyl acrylate
Styrene
n-Butyl acrylate
Styrene
n-Butyl vinyl ether
Cyclohexyl vinyl ether
t-Butyl vinyl ether
n-Butyl acrylate
n-Butyl acrylate
Styrene
61 (26/26/48)
92f
90f
96d
61
76 (50/21/29)
89 (41/23/36)
32 (35/35/30)
93
50c
94
Styrene
43c
n-Butyl vinyl ether
n-Butyl acrylate
n-Butyl acrylate
Styrene
n-Butyl vinyl ether
n-Butyl acrylate
n-Butyl acrylate
Styrene
87 (54/20/26)
96
55c
80
86 (95/4/1)
87
56c
96
Styrene
74c
n-Butyl vinyl ether
Cyclohexyl vinyl ether
4-Vinylpyridine
n-Butyl acrylate
n-Butyl acrylate
Styrene
n-Butyl vinyl ether
n-Butyl acrylate
n-Butyl acrylate
n-Butyl acrylate
Styrene
2-Vinylpyridine
2-Vinylpyridine
4-Vinylpyridine
4-Vinylpyridine
4-Vinylpyridine
68 (89/3/8)
71 (93/2/5)
95
100c
34
50
25 (95/5/0)
95f
65g
68h
61h
85
Iodobenzene
Iodobenzene
Iodobenzene
4-Bromobenzophenone
24c
98c
40
68
Conditions: catalyst [Pd(C3H5)Cl]2/tedicyp 1/2 see Ref. 7a, ArX (1 equiv.), alkene (2 equiv.), K2CO3 (2 equiv.), DMF, 140°C, 24 h, under argon,
isolated yields.
a For the reactions with n-butyl acrylate, styrene, 2-vinylpyridine, 4-vinylpyridine, E isomer was obtained selectively (>95%); for the reactions with
vinyl ethers the regio- and stereoselectivities are given in brackets (G/Z/E) (Scheme 1).
b The formation of 2,2%-bipyridine was also observed.
c GC or NMR yields.
d Reaction time: 48 h.
e Commercially available 4-bromopyridine hydrochloride was not used directly.
f Alkene 4 equiv., K2CO3 4 equiv., the diaddition products were obtained selectively.
g Alkene 4 equiv., K2CO3 4 equiv., the ratio monoaddition/diaddition products was 82/18.
h Reaction temp. 80°C.

5628
F. Berthiol et al. / Tetrahedron Letters 43 (2002) 5625–5628
4. For recent examples of Heck reaction catalysed by pal-
Acknowledgements
ladacycles, see: (a) Albisson, D.; Bedford, R.; Scully, P.
N. Tetrahedron Lett. 1998, 39, 9793; (b) Littke, A.; Fu,
G. J. Org. Chem. 1999, 64, 10; (c) Miyazaki, F.;
Yamaguchi, K.; Shibasaki, M. Tetrahedron Lett. 1999,
40, 7379; (d) Ohff, M.; Ohff, A.; Milstein, D. Chem.
Commun. 1999, 357; (e) Gai, X.; Grigg, R.; Ramzan, I.;
Sridharan, V.; Collard, S.; Muir, J. Chem. Commun.
2000, 2053; (f) Gruber, A.; Zim, D.; Ebeling, G.; Mon-
teiro, A.; Dupont, J. Org. Lett. 2000, 2, 1287.
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.
References
1. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chem-
istry; Pergamon: Amsterdam, 2000.
5. Herrmann, W. A.; Brossmer, C.; Reisinger, C.; Rier-
2. 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. Vinyl substitution with organopalladium intermedi-
ates. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; 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. Transition Metal
Catalysed Reactions; Davies, S. G.; Murahashi, S.-I.,
Eds.; Blackwell Science: Oxford, 1999; (e) Beletskaya, I.;
Cheprakov, A. Chem. Rev. 2000, 100, 3009; (f) With-
combe, N.; Hii (Mimi) K. K.; Gibson, S. Tetrahedron
2001, 57, 7449.
3. For examples of palladium-catalysed Heck reaction with
heteroaromatic compounds: (a) Sakamoto, T.; Arakida,
H.; Edo, K.; Yamanaka, H. Heterocycles 1981, 16, 965;
(b) Wada, A.; Yamamoto, J.; Hase, T.; Nagai, S.;
Kanatomo, S. Synthesis 1986, 7, 555; (c) Akita, Y.;
Noguchi, T.; Sugimoto, M.; Ohta, A. J. Heterocycl.
Chem. 1986, 23, 1481; (d) Wada, A.; Yasuda, H.;
Kanatomo, S. Synthesis 1988, 10, 771; (e) Hirooka, S.;
Tanbo, Y.; Takemura, K.; Hironori, N.; Matsuoka, T.;
Kuroda, S. Bull. Chem. Soc. Jpn. 1991, 64, 1431; (f)
Bumagin, N. A.; Bykov, V. V.; Sukhomlinova, L. I.;
Tolstaya, T. P.; Beletskaya, I. P. J. Organomet. Chem.
1995, 486, 259; (g) Wright, S. W.; Hageman, D. L.;
McClure, L. D. J. Heterocycl. Chem. 1998, 35, 717; (h)
Anson, M. S.; Mirza, A. R.; Tonks, L. W.; Williams, J.
M. J. Tetrahedron Lett. 1999, 40, 7147; (i) Iyer, S.;
Ramesh, S. Tetrahedron Lett. 2000, 41, 8981; (j)
Fournier, J.; Gozzi, C.; Lemaire, M. Tetrahedron Lett.
2002, 43, 1829.
8
meier, T.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3,
1357.
6. For a review on the synthesis of polypodal diphenylphos-
phine ligands, see: Laurenti, D.; Santelli, M. Org. Prep.
Proc. Int. 1999, 31, 245.
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.
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; (c) Feuerstein, M.;
Doucet, H.; Santelli, M. Tetrahedron Lett. 2002, 43, 2191.
10. The formation of 2,2%-bipyridine as side product has
already been observed: Sakamoto, T.; Arakida, H.; Edo,
K.; Yamanaka, H. Chem. Pharm. Bull. 1982, 30, 3647.
11. As a typical experiment, the reaction of 2-iodothiophene
(2.10 g, 10 mmol), n-butyl acrylate (2.60 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 (0.001 mmol) under argon affords the
corresponding product after extraction with dichloro-
methane, evaporation and filtration on silica gel (ether/
pentane 1/1) in 96% (2.02 g) isolated yield. 1H NMR
(300 MHz, CDCl3) l: 7.76 (d, 1H, J=15.7 Hz), 7.35 (d,
1H, J=5.1 Hz), 7.24 (d, 1H, J=3.5 Hz), 7.03 (dd, 1H,
J=5.1 and 3.5 Hz), 6.22 (d, 1H, J=15.7 Hz), 4.18 (t, 2H,
J=6.6 Hz), 1.66 (m, 2H), 1.40 (m, 2H), 0.94 (t, 3H,
J=7.2 Hz).