Suzuki coupling reactions of heteroarylboronic acids with aryl halides and arylboronic acids with heteroaryl bromides using a tetraphosphine/palladium catalyst

Article abstract of DOI:10.1055/s-2005-871951

cix,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/ [PdCl(C₃H₅)]² efficiently catalyses the Suzuki reaction of heteroarylboronic acids with aryl bromides and also the coupling of arylboronic acids with heteroaryl bromides. The coupling of thiopheneboronic acids, 3-furanboronic acid and 3-pyridineboronic acid with a variety of aryl bromides gave the corresponding adducts in good yields. However, in most cases, better results in terms of substrate/catalyst ratio were obtained for the reaction of heteroaryl bromides with arylboronic acids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871951

LETTER
2057
Suzuki Coupling Reactions of Heteroarylboronic Acids with Aryl Halides and
Arylboronic Acids with Heteroaryl Bromides Using a Tetraphosphine/
Palladium Catalyst
Suzuki
C
s
oupling
R
a
eactions belle Kondolff, Henri Doucet,* Maurice Santelli*
UMR 6180 CNRS and Université d’Aix-Marseille III: ‘Chirotechnologies: catalyse et biocatalyse’, Laboratoire de Synthèse Organique,
Faculté des Sciences de Saint Jérôme, Université d’Aix-Marseille III, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20,
France
Fax +33(4)91983865; E-mail: henri.doucet@univ.u-3mrs.fr; E-mail: m.santelli@univ.u-3mrs.fr
Received 17 May 2005
obtained in allylic substitution,16 Heck,17 Sonogashira18
Abstract: cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinometh-
and Suzuki reactions19 using this ligand. We have also de-
yl)cyclopentane/[PdCl(C3H5)]2 efficiently catalyses the Suzuki re-
scribed several results for the Suzuki coupling of heteroar-
action of heteroarylboronic acids with aryl bromides and also the
yl halides with arylboronic acids.20 However, we have not
coupling of arylboronic acids with heteroaryl bromides. The cou-
pling of thiopheneboronic acids, 3-furanboronic acid and 3-py- studied the reverse reaction using heteroarylboronic acids
ridineboronic acid with a variety of aryl bromides gave the
with aryl halides. In order to further establish the require-
corresponding adducts in good yields. However, in most cases,
ments for successful Suzuki coupling reactions for the
better results in terms of substrate/catalyst ratio were obtained for
synthesis of arylthiophenes, arylfuranes or arylpyridines
the reaction of heteroaryl bromides with arylboronic acids.
with our catalyst, we herein report on the relative reaction
rates for the coupling of heteroarylboronic acids with aryl
bromides and heteroaryl bromides with arylboronic acids.
Key words: heteroaryl bromides, arylboronic acids, Suzuki reac-
tion, heteroarylboronic acids
Ph2P
PPh2
Heterobiaryls have important biological properties and
their preparation is an important industrial goal. The pal-
Ph2P
PPh2
Tedicyp
ladium-catalysed cross-coupling reaction between het-
eroaryl halides and arylboronic acids provides a very
Figure 1
efficient method for the preparation of heterobiaryl deriv-
atives.1,2 The reverse reaction using heteroarylboronic ac- For this study, based on previous results,20 xylene was
ids and aryl halides has attracted less attention, and most used as the solvent and K2CO3 as the base. The reactions
of the results have been described with Pd(PPh3)4 as cata- were performed at 130 °C under argon in the presence of
lyst.3–6 However, this ligand can be labile under some cou-
a 1:2 ratio of [Pd(C3H5)Cl]2/Tedicyp as catalyst
pling conditions especially at elevated temperature and (Scheme 1). We first studied the reactivity of 2-
gives palladium black which is generally inactive. In re- thiopheneboronic acid, 3-thiopheneboronic acid and 3-
cent years, a few other catalysts have been tested in the furanboronic acid with a range of aryl bromides
Suzuki coupling of these heteroarylboronic acid deriva- (Scheme 1, Table 1).
tives.7–15 Fu et al. have reported the coupling of 2-
thiopheneboronic acid with 4-bromo-N,N-dimethyl-
The coupling of 2-thiopheneboronic acid with iodoben-
zene, bromobenzene, 4-bromoacetophenone, 4-bromo-
anisole or 2-bromotoluene gave the expected 2-aryl-
thiophenes in good yields in the presence of 1–5% catalyst
aniline using 0.5% Pd2(dba)3 and 1.2% P(t-Bu)3 as
catalyst.7 2-(2¢,6¢-Dimethoxybiphenyl)dicyclohexylphos-
phine with 2–3% Pd2(dba)3 is also an efficient catalyst for
(Table 1, entries 1, 2, 4, 6, 8 and 9). Similar reaction rates
the coupling of 3-pyridineboronic acid with aryl halides.8
were observed with electron-poor and electron-rich aryl
Dppf as ligand gave satisfactory results with a thiophene
bromides indicating that with this heteroarylboronic acid,
and a pyridineboronic acid.9,10 A few other coupling reac-
the oxidative addition of the aryl halide is not rate-limit-
tions using these heteroarylboronic acids have also been
ing. Higher reaction rates were observed for the coupling
described in the presence of palladium nanoparticles, sup-
reactions in the presence of 3-thiopheneboronic acid.
With 4-bromoacetophenone, 4-bromobenzaldehyde, 4-
ported catalysts or in ionic liquids.11–15
In order to obtain stable and efficient palladium catalysts, bromobenzonitrile, 4-bromoanisole or 2-bromotoluene
we have prepared the tetraphosphine ligand, cis,cis,cis- the reactions were performed using 0.4–0.1% catalyst
1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane
(Table 1, entries 11, 12, 16–21 and 25). Then, in order
or Tedicyp16 (Figure 1). We have already reported results to determine the must powerful method for the synthesis
of these compounds, we determined the reaction rates for
the coupling reactions using 2-bromothiophene or 3-bro-
mothiophene with a few arylboronic acids. In most cases,
much faster reactions were observed, and substrates/
SYNLETT 2005, No. 13, pp 2057–2061
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871951; Art ID: G15505ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
8
.2
0
0
5

2058
I. Kondolff et al.
LETTER
R
R
R
R
[Pd(C3H5)Cl]2 / Tedicyp
xylene, K2CO3, 130 °C
[Pd(C3H5)Cl]2 / Tedicyp
xylene, K2CO3, 130 °C
X
B(OH)2
S
+
or
+
B(OH)2
Br
B(OH)2
or
Br
or
S
N
S
N
N
X = I, Br
R = H, Me, OMe, MeCO, PhCO, CHO, CN, F
Scheme 1
catalyst ratios up to 1000000:1 have been used success- In summary, in the presence of the Tedicyp/palladium
fully (Table 1, entries 3, 5, 7, 10, 15, 24 and 26). However, complex, the Suzuki cross-coupling of some heteroaryl-
the functional groups on the arylboronic acid have an im- boronic acids such as 3-thiopheneboronic acid or 3-furan-
portant influence on the reaction rates. For example the boronic acid with aryl bromides can be performed with as
coupling of 2-bromothiophene with 4-acetylbenzene- little as 0.1% catalyst. On the other hand, with 2-
boronic acid and 4-methoxybenzeneboronic acids were thiopheneboronic acid and 3-pyridineboronic acid the re-
performed using 0.1% and 0.0001% catalyst, respectively actions are quite slow and were performed with 1–10%
(Table 1, entries 5 and 7).
catalyst. With these heteroarylboronic acid derivatives
similar reaction rates were generally observed in the pres-
ence of 4-bromoacetophenone or 4-bromoanisole indicat-
ing that the rate-limiting step of these reactions does not
seem to be the oxidative addition of the aryl halides to pal-
ladium. In order to obtain higher TONs for the synthesis
of these products, we also studied the reverse reactions us-
ing arylboronic acids and heteroaryl bromides. We ob-
served that in most cases, much higher reaction rates were
obtained for the coupling of bromothiophenes or 3-bro-
mopyridine with arylboronic acids. For this reason, for the
synthesis of arylthiophene or arylpyridine derivatives, the
boronic acid function should preferably be located on the
aryl and the halide on the heteroaryl rather than the
reverse.
The reaction rates using 3-furanboronic acid and aryl ha-
lides are similar to those obtained with 3-thiopheneboron-
ic acid. With this heteroarylboronic acid, iodobenzene, 4-
bromoacetophenone, 4-bromobenzonitrile or 2-bromotol-
uene gave the arylfuran adducts in good yields in the pres-
ence of 0.4–0.1% catalyst (Table 1, entries 27, 28, 30, 31
and 33–35). The reverse reaction using 3-bromofuran and
arylboronic acids also gave the expected 3-arylfurans in
the presence of 0.1–0.4% catalyst (Table 1, entries 29, 32
and 37). However, these reactions were performed at a
lower temperature (90 °C) due to the low boiling point of
3-bromofuran. We had previously reported that the cou-
pling of 5-bromo-2-furaldehyde with arylboronic acids
proceeds with very high TONs.20
A few reactions were also performed with 3-thiophene
and 3-furanboronic acids at lower temperatures (90 °C).
With 3-thiopheneboronic acid the reactions were slower,
but satisfactory TONs of 300 and 225 were obtained with
4-bromoacetophenone and 4-bromoanisole (Table 1, en-
tries 13, 14, 22 and 23). On the other hand, with 3-furan-
boronic acid, 2-bromotoluene was recovered unreacted
(Table 1, entry 36).
Acknowledgment
We thank the CNRS for providing financial support.
References
(1) For reviews on palladium-catalysed Suzuki coupling
reactions see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576,
147. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009. (d) Suzuki, A. J. Organomet. Chem. 2002,
653, 83. (e) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 4177.
(2) For examples of palladium-coupling reactions with
heteroaromatic substrates: Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon:
Amsterdam, 2000.
(3) For selected examples of palladium cross-coupling reactions
with thiopheneboronic acids: (a) Peters, D.; Hoernfeldt, A.-
B.; Gronowitz, S. J. Heterocycl. Chem. 1991, 28, 1613.
(b) Chamoin, S.; Houldsworth, S.; Kruse, C. G.; Bakker, W.
I.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4179.
(c) Zhang, J.; Aszodi, J.; Chartier, C.; L’hermite, N.;
Weston, J. Tetrahedron Lett. 2001, 42, 6683. (d)Langle, S.;
Abarbri, M.; Duchene, A. Tetrahedron Lett. 2003, 44, 9255.
(e) Vachal, P.; Toth, L. M. Tetrahedron Lett. 2004, 45, 7157.
Next, we studied the synthesis of 3-arylpyridines by cou-
pling 3-pyridineboronic acid with several aryl bromides
and also by the reaction of 3-bromopyridine with arylbo-
ronic acids (Table 2). Very slow reactions were observed
with 3-pyridineboronic acid, and 2–10% catalyst had to be
used in order to obtain high yields of adducts (Table 2, en-
tries 1, 3, 4, 6, 8, 10, 11, 13, 15 and 18). These results re-
vealed a minor substituent effect of the aryl bromide on
the reaction rate, indicating that again, with 3-pyridinebo-
ronic acid as coupling partner, the rate-limiting step of the
reaction is not the oxidative addition of the aryl bromide.
The reverse coupling reactions using 3-bromopyridine
and arylboronic acids gave much more satisfactory results
in terms of substrate/catalyst ratio. The reactions were
performed using 0.1–0.001% catalyst (Table 2, entries 2,
5, 7, 9, 12, 14, 16, 17, 19 and 20).
Synlett 2005, No. 13, 2057–2061 © Thieme Stuttgart · New York

LETTER
Suzuki Coupling Reactions
2059
Table 1 Suzuki Reaction with Thiophene and Furan Derivatives Catalysed by the Tedicyp/Palladium Complexa,21
Entry
Aryl halide
Arylboronic acid
Substrate/catalyst ratiob Product
Yield (%)c
1
2
3
4
5
6
7
Iodobenzene
2-Thiopheneboronic acid
2-Thiopheneboronic acid
Benzeneboronic acid
100:1
1
1
1
2
2
3
3
82 (96)
(47)
88
Bromobenzene
50:1
2-Bromothiophene
4-Bromoacetophenone
2-Bromothiophene
4-Bromoanisole
2-Bromothiophene
100000:1
100:1
2-Thiopheneboronic acid
4-Acetylphenylboronic acid
2-Thiopheneboronic acid
4-Methoxyphenylboronic acid
80 (86)
90
1000:1
50:1
81
1000000:1
85
8
9
2-Bromotoluene
2-Bromotoluene
2-Thiopheneboronic acid
2-Thiopheneboronic acid
20:1
50:1
4
4
87 (100)
(40)
10
2-Bromothiophene
2-Methylphenylboronic acid
100000:1
4
89
11
12
13
14
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
3-Thiopheneboronic acid
3-Thiopheneboronic acid
3-Thiopheneboronic acid
3-Thiopheneboronic acid
250:1
1000:1
250:1
5
5
5
5
77 (82)
(55)
(84)d
(30)d
1000:1
15
3-Bromothiophene
4-Acetylphenylboronic acid
250:1
5
86
16
17
4-Bromobenzaldehyde
4-Bromobenzaldehyde
3-Thiopheneboronic acid
3-Thiopheneboronic acid
250:1
1000:1
6
6
81 (90)
(45)
18
19
4-Bromobenzonitrile
4-Bromobenzonitrile
3-Thiopheneboronic acid
3-Thiopheneboronic acid
250:1
1000:1
7
7
85 (96)
(77)
20
21
22
23
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
3-Thiopheneboronic acid
3-Thiopheneboronic acid
3-Thiopheneboronic acid
3-Thiopheneboronic acid
250:1
1000:1
250:1
8
8
8
8
84 (97)
(42)
(90)d
0d
1000:1
24
25
26
3-Bromothiophene
2-Bromotoluene
4-Methoxyphenylboronic acid
3-Thiopheneboronic acid
1000000:1
1000:1
8
9
9
75
84 (90)
93
3-Bromothiophene
2-Methylphenylboronic acid
1000000:1
27
28
Iodobenzene
Iodobenzene
3-Furanboronic acid
3-Furanboronic acid
250:1
1000:1
10
10
83 (100)
(35)
29
3-Bromofuran
Benzeneboronic acid
1000:1
10
91 (100)d
30
31
4-Bromoacetophenone
4-Bromoacetophenone
3-Furanboronic acid
3-Furanboronic acid
250:1
1000:1
11
11
81 (98)
(84)
32
33
3-Bromofuran
4-Acetylphenylboronic acid
3-Furanboronic acid
250:1
250:1
11
12
87 (94)d
68
4-Bromobenzonitrile
34
35
36
2-Bromotoluene
2-Bromotoluene
2-Bromotoluene
3-Furanboronic acid
3-Furanboronic acid
3-Furanboronic acid
250:1
1000:1
100:1
13
13
13
81 (90)
(28)
0d
37
3-Bromofuran
2-Methylphenylboronic acid
250:1
13
70d
a Conditions: catalyst [Pd(C3H5)Cl]2/Tedicyp (1:2),16 ArX (1 equiv), arylboronic acid (2 equiv), K2CO3 (2 equiv), xylene, 20 h, 130 °C, under
argon.
b Substrate/catalyst ratio based on aryl halide.
c Isolated yields; yields in parenthesis correspond to GC and NMR yields.
d Reaction temperature: 90 °C
Synlett 2005, No. 13, 2057–2061 © Thieme Stuttgart · New York

2060
I. Kondolff et al.
LETTER
Table 2 Suzuki Reaction with Pyridine Derivatives Catalysed by the Tedicyp/Palladium Complexa,21
Entry
Aryl bromide
Arylboronic acid
Substrate/catalyst ratiob Product
Yield (%)c
1
2
3
4
5
6
7
8
9
Bromobenzene
3-Pyridineboronic acid
Benzeneboronic acid
33:1
14
14
15
16
16
17
17
18
18
75
3-Bromopyridine
4-Bromobenzophenone
3-Bromobenzaldehyde
3-Bromopyridine
4-Fluorobromobenzene
3-Bromopyridine
4-Bromoanisole
1000000:1
20:1
98e,20b
82 (100)
84 (100)
87 (100)
84
3-Pyridineboronic acid
3-Pyridineboronic acid
3-Formylphenylboronic acid
3-Pyridineboronic acid
4-Fluorophenylboronic acid
3-Pyridineboronic acid
4-Methoxyphenylboronic acid
20:1
100:1
10:1
100000:1
20:1
96e,20b
80
3-Bromopyridine
100000:1
8220b
10
11
2-Bromoacetophenone
2-Bromoacetophenone
3-Pyridineboronic acid
3-Pyridineboronic acid
20:1
50:1
19
19
80 (100)
(49)
12
13
14
15
3-Bromopyridine
2-Bromotoluene
2-Acetylphenylboronic acid
3-Pyridineboronic acid
1000:1
20:1
19
20
20
21
77
85 (100)
8720b
84
3-Bromopyridine
1-Bromonaphthalene
2-Methylphenylboronic acid
3-Pyridineboronic acid
10000:1
10:1
16
17
3-Bromopyridine
3-Bromopyridine
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
10000:1
100000:1
21
21
77
(56)
18
2,6-Dimethylbromobenzene
3-Pyridineboronic acid
20:1
22
85 (98)
19
20
3-Bromopyridine
3-Bromopyridine
Mesitylboronic acid
Mesitylboronic acid
1000:1
10000:1
23
23
91 (100)
(70)
a Conditions: catalyst [Pd(C3H5)Cl]2 /Tedicyp 1:2,16 ArBr (1 equiv), arylboronic acid (2 equiv), K2CO3 (2 equiv), xylene, 20 h, 130 °C, under
argon.
b Substrate/catalyst ratio based on the aryl halide.
c Isolated yields; yields in parenthesis correspond to GC and NMR yields.
d PhB(OH)2 (1.5 equiv), 115 h.
e PhB(OH)2 (1.5 equiv), 90 h.
(4) For selected examples of palladium cross-coupling reactions
with furanboronic acids: (a) Yang, Y. Synth. Commun.
1989, 19, 1001. (b) Finch, H.; Reece, D. H.; Sharp, J. T. J.
Chem. Soc., Perkin Trans. 1 1994, 1193. (c) Padwa, A.;
Zanka, A.; Cassidy, M. P.; Harris, J. M. Tetrahedron 2003,
59, 4939. (d) Kotha, S.; Kashinath, D.; Lahiri, K.; Sunoj, R.
B. Eur. J. Org. Chem. 2004, 4003.
(5) For selected examples of palladium cross-coupling reactions
with pyridineboronic acids: (a) Goodall, W.; Wild, K.; Arm,
K. J.; Williams, J. A. G. J. Chem. Soc., Perkin Trans. 2 2002,
166. (b) Daku, K. M. L.; Newton, R. F.; Pearce, S. P.; Vile,
J.; Williams, J. M. J. Tetrahedron Lett. 2003, 44, 5095.
(c) Rebstock, A.-S.; Mongin, F.; Trecourt, F.; Queguiner, G.
Tetrahedron 2003, 59, 4973.
(8) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S.
L. J. Am. Chem. Soc. 2005, 127, 4685.
(9) Morris, G. A.; Nguyen, S. T. Tetrahedron Lett. 2001, 42,
2093.
(10) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(11) Solodenko, W.; Wen, H.; Leue, S.; Stuhlmann, F.;
Sourkouni-Argirusi, G.; Jas, G.; Schönfeld, H.; Kunz, U.;
Kirschning, A. Eur. J. Org. Chem. 2004, 3601.
(12) Uozumi, Y.; Nakai, Y. Org. Lett. 2002, 4, 2997.
(13) Miao, W.; Chan, T. H. Org. Lett. 2003, 5, 5003.
(14) Atrash, B.; Reader, J.; Bradley, M. Tetrahedron Lett. 2003,
44, 4779.
(15) Tzschucke, C. C.; Markert, C.; Glatz, H.; Bannwarth, W.
Angew. Chem. Int. Ed. 2002, 41, 4500.
(6) Appukkuttan, P.; Orts, A. B.; Chandran, R. P.; Goeman, J.
L.; Van der Eycken, J.; Dehaen, W.; Van der Eycken, E. Eur.
J. Org. Chem. 2004, 3277.
(7) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(16) Laurenti, D.; Feuerstein, M.; Pèpe, G.; Doucet, H.; Santelli,
M. J. Org. Chem. 2001, 66, 1633.
(17) Feuerstein, M.; Doucet, H.; Santelli, M. J. Org. Chem. 2001,
66, 5923.
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Biomol. Chem. 2003, 2235.
Synlett 2005, No. 13, 2057–2061 © Thieme Stuttgart · New York

LETTER
Suzuki Coupling Reactions
2061
(19) (a) Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucet, H.;
Santelli, M. Chem. Commun. 2001, 325. (b) Feuerstein, M.;
Laurenti, D.; Doucet, H.; Santelli, M. Synthesis 2001, 2320.
(c) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron
Lett. 2001, 42, 6667. (d) Feuerstein, M.; Doucet, H.;
Santelli, M. Synlett 2001, 1458. (e)Feuerstein, M.;Berthiol,
F.; Doucet, H.; Santelli, M. Synlett 2002, 1807. (f)Berthiol,
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60, 3813. (i) Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli,
M. Eur. J. Org. Chem. 2004, 1075. (j) Kondolff, I.;
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2004, 689, 2786.
(20) (a) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron
Lett. 2001, 42, 5659. (b) Feuerstein, M.; Doucet, H.;
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(21) A typical experiment (Table 1, entry 11): Thiophene-3-
boronic acid (0.256 g, 2 mmol), 4-bromo-acetophenone
(0.199 g, 1 mmol) and K2CO3 (0.276 g, 2 mmol) at 130 °C
over 20 h in xylene (3 mL) in the presence of cis,cis,cis-
1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/
[PdCl(C3H5)]2 complex (0.004 mmol) under argon afforded
the corresponding product after evaporation and filtration
through silica gel; yield: 0.156 g, 77%. 1H NMR (300 MHz,
CDCl3): d = 7.98 (d, 2 H, J = 8.3 Hz), 7.68 (d, 2 H, J = 8.3
Hz), 7.57 (dd, 1 H, J = 2.5, 1.7 Hz), 7.43–7.40 (m, 2 H), 2.61
(s, 3 H).
Synlett 2005, No. 13, 2057–2061 © Thieme Stuttgart · New York