Sonogashira cross-coupling reactions with heteroaryl halides in the presence of a tetraphosphine-palladium catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.01.044

Heteroaryl halides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2, 3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of heteroaryl halides such as pyridines, quinolines, a pyrimidine, an indole, a thiophene, or a thiazole have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene and a range of alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.

Full text of DOI:10.1016/j.tetlet.2005.01.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1717–1720
Sonogashira cross-coupling reactions with heteroaryl halides in
the presence of a tetraphosphine–palladium catalyst
*
Marie Feuerstein, Henri Doucet and Maurice Santelli
*
Laboratoire de Synth e` se Organique, UMR 6180 CNRS and Universit e´ d’Aix-Marseille III: ‘Chirotechnologies: catalyse et
biocatalyse’, Facult e´ des Sciences de Saint J e´ r oˆ me, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 30 November 2004; revised 7 January2005; accepted 11 January2005
Available online 28 January2005
Abstract—Heteroaryl halides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C
1
3 5 2
H )] /cis,cis,cis-
,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of heteroaryl halides such as pyridines, quinolines,
a pyrimidine, an indole, a thiophene, or a thiazole have been used successfully. The reaction also tolerates several alkynes such
as phenylacetylene and a range of alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.
Ó 2005 Elsevier Ltd. All rights reserved.
2
6,27
The cross-coupling palladium-catalysed reactions be-
tween aryl halides and alkynes are among the most
of 2-iodothiophene using 3% of palladium catalyst.
Finally, one of the best catalyst reported is a palladium
(II) complex containing a ferrocene-based phosphin-
imine-phosphine ligand which gave good yields using
1
–3
widelyused methodologies in organic s yn thesis.
cent years, the efficiency of several palladium catalysts
In re-
4
–11
28
for these reactions has been described.
On the other
2-iodo- or 2-bromothiophene. Despite these recent ad-
hand, the reaction of heteroaryl halides has attracted
less attention, and suffers generallyfrom high catal ys t
loadings. A few ligands have been successfullyemployed
vances, there still remained a need for a general proto-
col; moreover, the efficiencyof tetraphosphine ligands
for the alkynylation of heteroaryl halides has not been
reported.
1
2–29
for the reaction with these substrates.
The first one
was triphenylphosphine, however, the catalyst formed
byassociation of this ligand with palladium complexes
is not veryefficient in terms of the ratio substrate/cata-
In order to find stable and efficient palladium catalysts,
we have prepared the tetrapodal phosphine ligand, cis,
cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclo-
1
2–22
lyst and 3–10% catalyst had to be used.
Recently,
3
0
new palladium catalysts have also been successfully
employed for the alkynylation reactions with heteroaryl
pentane or Tedicyp (Fig. 1) in which the four diph-
enylphosphinoalkyl groups are stereospecifically bound
to the same face of the cyclopentane ring. We have al-
readyreported the results obtained in all yl ic substitu-
2
3–29
halides.
interesting results have been recentlyreported.
In the monophosphine ligand series,
3–25
2
3
0
31
32
Soheili et al. described that P(t-Bu) associated to [(al-
3
lyl)PdCl] is a good ligand for the reaction of 3-bromo-
2
tion, in Heck reaction, in Suzuki cross-coupling
3
3–36
and in Sonogashira reaction
using Tedicyp as li-
pyridine or 3-bromothiophene with phenylacetylene,
gand. For example, we obtained a turnover number
(TON) of 2,800,000 for the coupling of 3,5-bis(trifluo-
2
3
without CuI, at room temperature. Buchwald ob-
tained high yields using 1% of a catalyst derived from
PdCl (CH CN) and a bulkyand electron-rich ortho-
3
3
romethyl)bromobenzene with phenyl-acetylene. We
have also recentlyreported the coupling of alk yn es with
a range of aryl chlorides with as little as 0.01% cata-
2
3
2
2
4
biphenylphosphane ligand. With the imidazolium car-
bene ligand good results were obtained for the coupling
3
5
lyst. Here, we wish to report on the efficiencyof
Keywords: Palladium; Catalysis; Heteroaryl halide; Alkyne; Sonogash-
ira reaction; Tetraphosphine.
Ph2P
PPh
2
Ph P
2
PPh
2
*
Corresponding authors. Tel.: +33 4 91 28 84 16; fax: +33 4 91 98 38
5 (H.D.); tel.: +33 4 91 28 88 25 (M.S.); e-mail addresses:
henri.doucet@univ.u-3mrs.fr; m.santelli@univ.u-3mrs.fr
Tedicyp
6
Figure 1.
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.044

1718
M. Feuerstein et al. / Tetrahedron Letters 46 (2005) 1717–1720
[
Pd(C3H5)Cl]2/
Tedicyp
H
+
X Ar
Ar
K2CO3, CuI, DMF,
00 °C
1
1
-11
Scheme 1.
Tedicyp ligand for the reaction of heteroaryl halides with
terminal alkynes such as phenylacetylene or alk-1-ynols.
vityof the nitrogen atom, the a and the c positions of
halo pyridines should be most susceptible to do the oxi-
dative addition to palladium (0). In fact, we observed
similar reactions rates for the 2-, 3- and 4-bromopyri-
dines for a ratio S/C = 10,000 (Table 1, entries 1, 3
and 7). These results seem to indicate that the oxidative
addition of bromopyridines to palladium is not the rate-
limiting step of the reaction with this catalyst. We have
also investigated the influence of the nature of the halo-
gen on the reactivityof p yr idines. As expected, the oxi-
dative addition of 2- and 4-chloropyridines to Pd(0) is
faster than for 3-chloropyridine (Table 1, entries 2, 4–
5, 8). In fact, it was not possible to cross-couple 3-chlo-
ropyridine with phenylacetylene under conditions simi-
lar to those employed for 3-bromopyridine (Table 1,
entry4), but a conversion of 90% was obtained using
3
3–36
For this study, based on our previous results,
DMF
was chosen as the solvent and potassium carbonate as
the base. The reactions were generallyperformed at
1
00 °C under argon in the presence of a ratio 1/2 of
[Pd(C H )Cl] /Tedicyp as catalyst and 5% copper (I)
iodide as co-catalyst.
3
5
2
First, we tried to couple phenylacetylene with a range of
heteroaryl halides (Scheme 1, Table 1). We studied the
influence of the position of the bromo-substituent on
pyridines on the reaction rate. Due to the electronegati-
Table 1. Cross-coupling reactions of heteroaryl halides with phenyl-
acetylene (Scheme 1)
1
1
% catalyst without addition of CuI at 130 °C (Table
, entry5). Then, we studied the reactivityof haloquino-
37
EntryArX
Ratio substrate/
catalyst
Product Yield
a
number (%)
lines. We observed that the reactivityis similar to halo-
pyridines. 2-Chloroquinoline, 3-bromoquinoline and 4-
bromoisoquinoline led to the coupling products 4, 5
and 6 using 0.01% catalyst (Table 1, entries 9–12). Next,
we studied the influence of the position of the halogen
on thiophenes and we observed that 3-bromothiophene
gave a lower TON: 780 (Table 1, entry19) than 2-
bromothiophene: 5600 (Table 1, entry18).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2-Bromopyridine
2-Chloropyridine
3-Bromopyridine
3-Chloropyridine
3-Chloropyridine
10,000
1000
1
1
80
90
75
0
b
c
10,000
100
100
2
2
d
2
90
97
50
75
97
60
79
60
60
100
80
76
95
56
78
e
4-Bromopyridine
4-Bromopyridine
1000
3
e
c
c
10,000
1000
1000
3
e
4-Chloropyridine
2-Chloroquinoline
2-Chloroquinoline
3-Bromoquinoline
3
As expected, the reactions of bromothiophenes (p-
electron excessive heterocycles) with phenylacetylene
are more sensitive to the halogen position than bromo-
pyridines (p-electron deficient heterocycles). With bromo-
thiophenes the oxidative addition step is probably
rate-limiting.
4
0
1
2
3
4
5
6
7
8
9
10,000
10,000
4
5
4-Bromoisoquinoline 10,000
5-Bromoindole
6
10,000
1000
7
c
5-Bromopyrimidine
5-Bromopyrimidine
2-Bromothiazole
2-Bromothiophene
2-Bromothiophene
3-Bromothiophene
8
10,000
10,000
1000
8
9
Bromo-substituted indole, pyrimidine and thiazole
which have the potential to bind to palladium through
nitrogen or sulfur are also suitable substrates for Sono-
gashira reactions. TONs between 6000 and 8000 were
obtained for the couplings of 5-bromoindole, 5-bromo-
pyrimidine and 2-bromothiazole with phenylacetylene
b
c
10
10
11
10,000
1000
b
a
Conditions: catalyst see Ref. 30, heteroaryl halide (1 equiv), phenyl-
acetylene (2 equiv), K CO
(2 equiv), CuI (0.05 equiv), DMF, 100 °C,
0 h.
2
3
2
(
Table 1, entries 13–16).
b
The reaction performed under similar conditions using [Pd(C
without Tedicyp ligand does not proceed.
GC and NMR yield.
3 5 2
H )Cl]
c
d
e
Having demonstrated that heteroaryl halides can be effi-
ciently cross-coupled with phenylacetylene, we investi-
gated the scope of this reaction using four alk-1-ynols
(Scheme 2, Table 2).
Reaction performed without CuI at 130 °C.
-Bromo- or 4-chloropyridine hydrochlorides were used directly with
4
3
equiv of K CO
2
3
.
[
Pd(C3H5)Cl]2/Tedicyp
R1
H
X Ar
R1
Ar
+
K2CO3, DMF, CuI, 100 °C
R1 = -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH
1
2-32
Scheme 2.

M. Feuerstein et al. / Tetrahedron Letters 46 (2005) 1717–1720
1719
37
Table 2. Cross-coupling reactions of heteroaryl halides with various alk-1-ynols (Scheme 2)
a
Entry
ArX
Alkyne
Ratio substrate/catalyst
Product number
Yield (%)
1
2
3
4
5
6
7
8
9
2-Bromopyridine
2-Chloropyridine
3-Iodopyridine
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
Propargyl alcohol
But-3-yn-1-ol
5000
100
12
12
13
13
13
14
14
15
15
16
17
18
19
19
20
20
21
22
23
24
25
26
27
28
29
30
30
31
31
32
90
97
80
90
30
60
86
80
49
85
65
55
90
20
90
80
72
98
90
99
75
60
52
95
92
97
50
58
70
15
100,000
100
100
3-Bromopyridine
3-Chloropyridine
c
4-Bromopyridine
1000
100
c
4-Chloropyridine
2-Chloroquinoline
2-Chloroquinoline
2-Bromothiazole
2-Bromothiophene
3-Bromothiophene
2-Bromopyridine
2-Bromopyridine
3-Iodopyridine
100
b
1000
100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
100
100
1000
10,000
1,000,000
1000
1000
100
b
But-3-yn-1-ol
But-3-yn-1-ol
3-Bromopyridine
4-Chloropyridine
But-3-yn-1-ol
But-3-yn-1-ol
c
3-Bromoquinoline
2-Chloroquinoline
5-Bromoindole
But-3-yn-1-ol
But-3-yn-1-ol
1000
100
But-3-yn-1-ol
But-3-yn-1-ol
5-Bromopyrimidine
2-Bromothiazole
1000
1000
1000
100
But-3-yn-1-ol
But-3-yn-1-ol
But-3-yn-1-ol
2-Bromothiophene
3-Bromothiophene
3-Bromopyridine
4-Bromoisoquinoline
4-Bromoisoquinoline
2-Iodothiophene
Pent-4-yn-1-ol
Pent-4-yn-1-ol
Pent-4-yn-1-ol
Pent-4-yn-1-ol
Pent-4-yn-1-ol
Hex-5-yn-1-ol
1000
100
b
b
1000
10,000
1000
10,000
2-Bromothiophene
4-Bromoisoquinoline
a
b
c
Conditions: catalyst see Ref. 30, heteroaryl halide (1 equiv), alkyne (2 equiv), K
GC and NMR yield.
-Bromo- or 4-chloropyridines hydrochloride were used directly with 3 equiv of K
2
CO
3
(2 equiv), CuI (0.05 equiv), DMF, 100 °C, 20 h.
4
2
CO
3
.
First, we studied the reactivityof proparg yl alcohol with
some heteroaryl halides. The results described in Table 2
shown that lower reactions rates were obtained using
this alk-1-ynol than with phenylacetylene (Table 2,
entries 1–12). Only2-bromop yr idine ( Table 2, entry1),
of heteroaromatics with several alkynes. Despite the
presence of heteroatoms, including N and S, that might
be expected to significantlyaffect the course of the Pd-
catalysed reaction of heteroaryl halides, a wide variety
of heteroaryl substrates have been successfully alkynyl-
ated. The position and the nature of the halide on the
heteroaromatic has an important effect on the reactions
rates. The reactions can be performed with as little as
0.01% with the most reactive heteroaryl bromides.
We believe that this system compares favourably with
other catalyst systems that have been reported for this
process.
4
9
-bromopyridine (entry 6) and 2-chloroquinoline (entry
) were coupled efficientlyusing 0.1% catal ys t. The best
result was obtained with 3-iodopyridine with a TON of
0,000 (Table 2, entry3). The other heteroar yl halides
8
required the presence of 1% catalyst in order to obtain
the desired products in good yields. The reactions with
but-3-yn-1-ol gave better results than with propargylic
alcohol. With the most reactive heteroaryl halides the
coupling products were obtained in good yields using
0
.1% catalyst (Table 2, entries 16–17, 19, 21–23). The
Acknowledgements
highest TON was obtained for the reaction of 3-iodo-
pyridine: 900,000 (Table 2, entry15). Much slower reac-
tions rates were observed with 3-bromoquinoline, 5-
bromoindole and 3-bromothiophene (Table 2, entries
We thank the CNRS and the ÔConseil G e´ n e´ ral des
Bouches-du-Rh oˆ ne, FrÕ for financial support and M.F.
is grateful to the Minist e` re de la Recherche et de la
Technologie for a grant.
1
8, 20, 24). Finally, we studied the reactivity of pent-4-
yn-1-ol and hex-5-yn-1-ol (Table 2, entries 25–30). These
reactions can be performed with the same amount of
catalyst than with but-3-yn-1-ol. A TON of 1500 was
obtained for the coupling of 4-bromoisoquinoline with
hex-5-yn-1-ol (Table 2, entry30).
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In conclusion, Tedicyp–palladium complex provides a
convenient catalyst for the cross-coupling of a variety

1720
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(see tables) during 20 h in DMF (10 mL) in the presence of
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4
drying (MgSO ), evaporation and filtration on silica gel.