Palladium-catalysed direct heteroarylations of heteroaromatics using esters as blocking groups at c2 of bromofuran and bromothiophene derivatives: A one-step access to biheteroaryls

Article abstract of DOI:10.1055/s-0031-1290453

Methyl 5-bromo-2-furoate and ethyl 5-bromothiophene-2-carboxylate have been found to be useful alternative reagents to 2-halofurans and 2-halothiophenes for the palladium-catalysed direct arylation of heteroaromatics. As their C5 is blocked by ester groups, the use of these substrates prevents the formation of dimers or oligomers, and therefore allows the formation of biheteroaryls in high yields. A very wide variety of heteroaromatics can be coupled with these two reagents. Moreover, with methyl 5-bromo-2-furoate, sequential catalytic C5 arylation, decarboxylation, catalytic C2-arylation reactions allowed the synthesis of 2,5-diarylated furan derivatives.

Full text of DOI:10.1055/s-0031-1290453

LETTER
▌2077
letter
Palladium-Catalysed Direct Heteroarylations of Heteroaromatics Using Esters
as Blocking Groups at C2 of Bromofuran and Bromothiophene Derivatives:
A One-Step Access to Biheteroaryls
One-Step Access to Biheteroaryls
Hai Yan Fu,a Liqin Zhao,b Christian Bruneau,b Henri Doucet*b
a
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064,
P. R. of China
b
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes ‘Organométalliques, Matériaux et Catalyse’, Campus de
Beaulieu, 35042 Rennes, France
Fax +33(2)23236939; E-mail: henri.doucet@univ-rennes1.fr
Received: 23.04.2012; Accepted after revision: 26.06.2012
Abstract: Methyl 5-bromo-2-furoate and ethyl 5-bromothiophene-
N
2-carboxylate have been found to be useful alternative reagents to
2-halofurans and 2-halothiophenes for the palladium-catalysed di-
rect arylation of heteroaromatics. As their C5 is blocked by ester
groups, the use of these substrates prevents the formation of dimers
or oligomers, and therefore allows the formation of biheteroaryls in
high yields. A very wide variety of heteroaromatics can be coupled
with these two reagents. Moreover, with methyl 5-bromo-2-furoate,
sequential catalytic C5 arylation, decarboxylation, catalytic C2-ar-
ylation reactions allowed the synthesis of 2,5-diarylated furan de-
rivatives.
S
N
N
H
N
O
N
NH2
HO
Ph
thiabendazol
lificiguat
N
N
N
N
O
R
N
N
preladenant
Figure 1
Key words: methyl 5-bromo-2-furoate, ethyl 5-bromothiophene-2-
carboxylate, palladium, direct arylation, heteroaromatics, bihetero-
aryls
occurs via a base-assisted deprotonation of the azole de-
rivatives followed by arylation.6 On the other hand, the
direct heteroarylation via ‘concerted metallation deprot-
onation’ mechanism, using halothiophenes or halofurans
has attracted less attention.7–11 The direct arylation with 5-
substituted 2-halofurans or 2-halothiophenes generally
gives the coupling products in quite good yields.7–9 On the
other hand, in the presence of unsubstituted 2-halothio-
phenes, the formation of dimers or oligomers is possible
(Scheme 1, top).10 This might explain the moderate yields
obtained for the coupling of 2-bromothiophene with 1,2-
dimethylimidazole (45%),10a or with 3,4-ethylenedioxy-
thiophene (40%).10c To our knowledge, direct heteroary-
lations using unsubstituted 2-halofurans have not been
described. This is certainly due to the limited access to 2-
halofurans. Moreover, the low boiling point of 2-bromo-
furan (52 °C) makes its handling not very convenient.
One of the most classical methods to prepare biheteroaryl
derivatives is to employ an heteroaryl halide with an or-
ganometallic heteroaryl derivative using a palladium cat-
alyst.1 However, these reactions require the preliminary
preparation of organometallic derivatives such as
HetArB(OR)2, HetArZnX, HetArMgX, or HetArSnR3
which might be tricky in several cases due to the poor sta-
bility of some of these heteroaromatics. Moreover, these
couplings provide either an organometallic or a salt (MX)
as byproduct.
As several biheteroaryl derivatives such as thiabendazol,
lificiguat, or preladenant have been found to present use-
ful bioactivities (Figure 1), we assumed that the discovery
of a simpler procedure for the preparation of a large vari-
ety of heteroarylated heteroarenes would provide a pow-
erful tool for pharmaceutical researchers.
To our knowledge, direct arylations using 5-bromo-2-
furoate or 5-bromothiophene-2-carboxylate have not been
reported. The use of these reactants, which are commer-
cially available, would certainly avoid the formation of
polyfurans or polythiophenes as side products. Moreover,
methyl 5-bromofuroate display a much higher boiling
point than 2-bromofuran (181 °C vs. 52 °C), allowing to
perform the reaction in classical glassware instead of au-
toclaves. Finally, the functionalisation of such esters to in-
troduce aryl, vinyl, alkyl, carbonyl, or even sulfide
substituents should be possible.12
In recent years, the palladium-catalysed direct arylation of
heteroaromatics with aryl halides proved to be an ex-
tremely powerful method for the synthesis of arylated
heteroaromatics.2–4 The palladium-catalysed direct het-
eroarylation at C2 of oxazole, thiazole, or imidazole de-
rivatives with halothiophenes also proceed nicely in
several cases.5 With these reactants the reaction certainly
SYNLETT 2012, 23, 2077–2082
Advanced online publication: 08.08.2012
Here, we wish to report on the palladium-catalysed direct
arylation of a set of heteroaromatics using esters as block-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290453; Art ID: ST-2012-D0352-L
© Georg Thieme Verlag Stuttgart · New York

2078
H. Y. Fu et al.
LETTER
tive was observed, and the desired coupling product 1 was
isolated in 71% yield (Table 1, entry 1). Moreover, no sig-
nificant amount of decarboxylated product was formed.12
Then, we extended the scope of the heteroarylation of
methyl 5-bromofuroate to a variety of thiophene deriva-
tives. Thiophenes substituted at C2 by methyl, acetyl, pro-
tected acetyl, nitrile, or ester gave the C5-heteroarylated
furans 2–6 in 75–83% yields (Table 1, entries 2–6). Sev-
eral furan derivatives were also employed successfully to
provide 2,2′-bifuranyl derivatives. For example, in the
presence of methyl 2-methylfuran-3-carboxylate, the de-
sired product 10 was produced in 84% yield (Table 1, en-
try 10). The monoarylation of 1-methylpyrrole or 1-
phenylpyrrole was also successful, and led to 13 and 14 in
77% and 79% yields, respectively (Table 1, entries 13 and
14). For these two reactions, a larger excess of pyrrole de-
rivative was employed in order to avoid the formation of
diheteroarylation products. The heteroarylation at C4 of
3,5-dimethylisoxazole or 1,3,5-trimethylpyrazole gave 17
and 18 in 88% and 91% yields, respectively (Table 1, en-
tries 17 and 18). Finally, a C2-substituted indole deriva-
tive was arylated at C3 to provide 19 in 81% yield (Table
1, entry 19).
previous work
[Pd]
Z
Z
S
H
H
H
Br
+
base
Y
Y
S
Z
Y
not reported
[Pd]
H
O
Br
H
base
O
Bp 52 °C
Z
decarboxylation
this work
[Pd]
Z
Z
H
Y
X
CO2R
+
Y
base
[Pd]
Br
CO2R
X
base, ArBr
X
Ar
blocked position
Y
X = O or S
Y = O, NR or S
Z = C or N
Scheme 1
ing groups in C5 position of 2-bromofuran and 2-bromo-
thiophene derivatives.
CO2Me
Br
First, we examined the reactivity of methyl 5-bromofu-
roate for the palladium-catalysed direct arylation of 2-iso-
butylthiazole using 1 mol% Pd(OAc)2 as the catalyst,
DMAc as the solvent, and KOAc as the base (Scheme 2,
Table 1, entry 1). These conditions had been previously
found operative for similar reactions.4a,d Using these con-
ditions, a complete conversion of the bromofuran deriva-
O
Z
Pd(OAc)2 (1 mol%)
R
+
O
CO2Me
DMAc, KOAc,
120 °C, 16 h
Y
Z
R
H
1–19
Y
Scheme 2
Table 1 Palladium-Catalysed Direct Arylation of Heteroarenes with Methyl 5-Bromofuroate (Scheme 2)a,13
Entry
Heteroarene
Product
Yield (%)b
71
N
N
1
1
S
O
CO2Me
S
2
3
2
3
83
81
S
O
S
CO2Me
S
O
S
CO2Me
O
O
O
O
S
O
4
4
81
S
CO2Me
O
O
5
6
5
6
76
75
EtO2C
NC
S
O
S
CO2Me
EtO2C
NC
S
O
S
CO2Me
Synlett 2012, 23, 2077–2082
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Step Access to Biheteroaryls
2079
Table 1 Palladium-Catalysed Direct Arylation of Heteroarenes with Methyl 5-Bromofuroate (Scheme 2)a,13 (continued)
Entry
7
Heteroarene
Product
Yield (%)b
55
7
Cl
S
S
O
CO2Me
Cl
8
9
8
9
63
79
S
O
CO2Me
CO2Me
S
O
O
O
MeO2C
MeO2C
10
10
84
O
O
CO2Me
O
AcO
11
12
11
12
78
71
AcO
O
O
O
CO2Me
CO2Me
EtO2C
O
O
O
EtO2C
13
14
15
N
13
14
15
77c
79c
75
N
O
O
CO2Me
Me
Me
N
N
CO2Me
Ph
Ph
MeO2C
N
N
N
O
CO2Me
MeO2C
Me
Me
N
N
O
16
17
16
17
90
88
N
CO2Me
N
O
N
O
O
CO2Me
N
N
N
18
19
18
19
91
81
N
O
Me
Me
CO2Me
N
N
O
CO2Me
Ph
Ph
a Conditions: Pd(OAc)2 (0.01 mmol), methyl 5-bromofuroate (1 mmol), heteroarene (2 mmol), KOAc (2 mmol), DMAc, 16 h, 120 °C.
b Isolated yields.
c Pyrrole derivative (4 mmol).
Then, we examined the reaction of methyl 5-bromofu- 2,2′-bithiophenyl is also possible. However, from one
roate with 2,2′-bithiophenyl (Scheme 3). Our objective equivalent of methyl 5-bromofuroate and 1.5 equivalents
was to obtain the monoarylated compound 20. In the of 2,2′-bithiophenyl in the presence of 2 mol% catalyst, 20
course of this reaction, the formation of 5,5′-diarylated
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2077–2082

2080
H. Y. Fu et al.
LETTER
was obtained in 73% yield. Only traces of diarylated 2,2′-
bithiophenyl were detected by GC–MS analysis.
Table 2 Palladium-Catalysed Direct Arylation of Heteroarenes with
Ethyl 5-Bromothiophene-2-carboxylate (Scheme 5)a,13
Entry Heteroarene
Product
Yield
(%)b
CO2Me
Br
O
(1 equiv)
+
PdCl(C3H5)(dppb)
(2 mol%)
N
N
S
O
CO2Me
1
22
92
DMAc,
S
S
S
CO2Et
S
KOAc (2 equiv),
120 °C, 16 h
20 73%
S
S
(1.5 equiv)
2
3
23
24
78
61
S
S
S
CO2Et
Scheme 3
NC
O
S
S
S
As carbons C2 and C5 of 1-methylpyrrole are much more
reactive than positions C3 and C4,4f we could expect the
formation of the 2,5-diheteroarylated pyrrole in the pres-
ence of an excess of methyl 5-bromofuroate as the cou-
pling partner. Indeed, product 21 was obtained in 46%
yield using 2 mol% Pd(OAc)2 as the catalyst (Scheme 4).
CO2Et
NC
O
S
4
5
6
25
26
27
52
75c
87
CO2Et
O
O
N
N
S
CO2Et
Me
N
Me
CO2Me
Br
O
O
Pd(OAc)2
(2 mol%)
O
MeO2C
N
CO2Me
(6 equiv)
+
N
N
S
N
DMAc,
KOAc (3 equiv),
120 °C, 16 h
CO2Et
Me
21 46%
N
Me
(1 equiv)
N
O
N
O
7
28
90
S
Scheme 4
CO2Et
a Conditions: Pd(OAc)2 (0.01 mmol), ethyl 5-bromothiophene-2-car-
boxylate (1 mmol), heteroarene (2 mmol), KOAc (2 mmol), DMAc,
16 h, 120 °C.
Next, we studied the coupling of ethyl 5-bromothiophene-
2-carboxylate with seven heteroarenes (Scheme 5, Table
2). The reaction with 2-isobutylthiazole gave 22 in a very
high yield (Table 2, entry 1). Satisfactory results were also
obtained with 2-methylthiophene and thiophene-2-carbo-
nitrile. The desired 2,2′-bithiophenyl derivatives 23 and
24 were obtained in 78% and 61% yields, respectively. A
moderate yield for 25 was obtained in the presence of 1-
(furan-2-yl)butan-1-one, due to the formation of side
products (Table 2, entry 4). Again, the use of a large ex-
cess of 1-methylpyrrole allowed the synthesis of the
monoarylated pyrrole 26 in good yield (Table 2, entry 5).
Finally, both imidazo[1,2-a]pyridine and 3,5-dimethyl-
isoxazole were employed. In both cases, very high yields
of the desired coupling products 27 and 28 were obtained
(Table 2, entries 6 and 7). It should be noted that, in all
cases, no significant decarboxylation of the thiophene de-
rivatives occurred in the course of these reactions.
b Isolated yields.
c Pyrrole derivative (4 mmol).
2-furoates.12,14,15 We observed that the treatment of 17 by
KOAc and K2CO3 as bases at 150 °C in the presence of 4-
bromobenzonitrile or 4-bromobenzaldehyde gave the
coupling products 29 and 30 in 70% and 61% yields, re-
spectively. Using the same conditions, the reaction of 16
with 4-bromobenzonitrile led to 31 in 77% yield (Scheme
6).
Pd(OAc)2 (2 mol%)
R
Br
R
N
DMAc,
O
O
KOAc (2 equiv)
K2CO3 (2 equiv)
150 °C, 16 h
(1 equiv)
+
R
Product Yield (%)
Finally, we examined the functionalisation of carbon C2
by decarboxylative coupling of some of our 5-heteroaryl-
N
O
O
CN
CHO
70
61
29
30
MeO2C
17 (1.5 equiv)
CO2Et
Br
S
or
NC
N
Z
N
Pd(OAc)2 (1 mol%)
R
+
O
S
O
CO2Et
MeO2C
N
DMAc, KOAc,
120 °C, 16 h
Y
N
Z
R
22–28
16 (1.5 equiv)
H
31 77%
Y
Scheme 6
Scheme 5
Synlett 2012, 23, 2077–2082
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Step Access to Biheteroaryls
2081
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In summary, we have demonstrated that the ester group
can be advantageously employed as blocking group on
some heteroaryl bromides in the course of the direct het-
eroarylation. Both methyl 5-bromofuroate and ethyl 5-
bromothiophene-2-carboxylate, using 1 mol% Pd(OAc)2
as the catalyst with KOAc as the base and DMAc as the
solvent at 120 °C generally led to high yields of the bihet-
eroaryl derivatives. Under these conditions, only traces of
in situ decarboxylation products were observed. Methyl 5-
bromofuroate represents an alternative reagent to 2-bro-
mofuran which is not easily accessible and difficult to
handle. In the presence of KOAc/K2CO3 as bases at
150 °C, the decarboxylation of this furoate is possible.
This was demonstrated by its sequential catalytic C5 ary-
lation, decarboxylation, and catalytic C2 arylation. This
procedure is economically attractive as both methyl 5-
bromofuroate and ethyl thiophene-2-carboxylate are com-
mercially available. Another advantage is the reduction of
number of steps to prepare these bi- or polyheteroaryls.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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(13) Typical Experiment for the Synthesis of Products 1–19
and 22–28
The reaction of the heteroaryl bromide (1 mmol),
heteroarene (2 mmol), and KOAc (0.196 g, 2 mmol) at
120 °C during 16 h in DMAc (4 mL) with Pd(OAc)2 (2.24
(4) For selected examples from our laboratory, see: (a) Dong, J.
J.; Roger, J.; Požgan, F.; Doucet, H. Green Chem. 2009, 11,
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H. Y. Fu et al.
LETTER
heteroarene (1.5 mmol), KOAc (0.196 g, 2 mmol), and
K2CO3 (0.276 g, 2 mmol) at 150 °C during 16 h in DMAc
(4 mL) with Pd(OAc)2 (4.48 mg, 0.02 mmol), under argon
affords the coupling product after evaporation of the solvent
and purification on silica gel.
mg, 0.01 mmol), under argon affords the coupling product
after evaporation of the solvent and purification on silica gel.
Methyl 5-(2-Isobutylthiazol-5-yl)-furan-2-carboxylate
(1)
1H NMR (400 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.14 (d, J =
2.3 Hz, 1 H), 6.50 (d, J = 2.3 Hz, 1 H), 3.84 (s, 3 H), 2.81 (d,
J = 7.7 Hz, 2 H), 2.10–2.00 (m, 1 H), 0.94 (d, J = 7.7 Hz, 6
H). 13C NMR (100 MHz, CDCl3): δ = 171.0, 158.8, 150.3,
143.7, 139.8, 126.7, 119.9, 108.3, 52.0, 42.4, 29.8, 22.2.
Anal. Calcd (%) for C13H15NO3S (265.33): C, 58.85; H,
5.70. Found: C, 58.99; H, 5.57.
4-[5-(3,5-Dimethylisoxazol-4-yl)-furan-2-yl]benzonitrile
(29)
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.2 Hz, 2 H),
7.61 (d, J = 8.2 Hz, 2 H), 6.84 (d, J = 2.7 Hz, 1 H), 6.43 (d,
J = 2.7 Hz, 1 H), 2.60 (s, 3 H), 2.41 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 166.0, 157.5, 151.1, 146.9, 134.2, 132.7,
123.7, 118.9, 110.4, 109.7, 109.0, 108.0, 12.7, 11.8. Anal.
Calcd (%) for C16H12N2O2 (264.28): C, 72.72; H, 4.58.
Found: C, 72.57; H, 4.40.
(14) (a) Fu, H. Y.; Doucet, H. Eur. J. Org. Chem. 2011, 7163.
(b) Chen, L.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. Green
Chem. 2012, 14, 1111.
(15) Typical Experiment for the Synthesis of Products 29–31
The reaction of the heteroaryl bromide (1 mmol),
Synlett 2012, 23, 2077–2082
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