Palladium-catalyzed direct arylation using free NH2 substituted thiophene derivatives with inhibition of amination type reaction

Article abstract of DOI:10.1016/j.tet.2012.06.053

The palladium-catalyzed direct arylation at C2 or C5 of free NH₂ substituted thiophene derivatives was found to proceed in moderate to high yields using a variety of aryl halides. The choice of potassium acetate as the base was found to be crucial to inhibit the amination reaction and to promote the direct arylation.

Full text of DOI:10.1016/j.tet.2012.06.053

Tetrahedron 68 (2012) 7463e7471
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Palladium-catalyzed direct arylation using free NH2 substituted thiophene
derivatives with inhibition of amination type reaction
,
Fazia Derridj a, Karima Si Larbi a, Julien Roger b, Safia Djebbar a, Henri Doucet b
*
a
ꢀ
ꢀ
ꢀ
Laboratoire d’hydrometallurgie et chimie inorganique moleculaire, Faculte de Chimie, U.S.T.H.B. Bab-Ezzouar, Algeria
b
ꢀ
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes 1, “Catalyse et Organometalliques”, Campus de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed direct arylation at C2 or C5 of free NH2 substituted thiophene derivatives was
found to proceed in moderate to high yields using a variety of aryl halides. The choice of potassium
acetate as the base was found to be crucial to inhibit the amination reaction and to promote the direct
arylation.
Received 26 April 2012
Accepted 13 June 2012
Available online 28 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Catalysis
Thiophenes
Aryl halides
CeH bond functionalization
1. Introduction
Here, we wish to report on the scope of this reaction using a set
of electronically and sterically diverse aryl halides. The regiose-
Heteroarenes bearing aryl substituents display important bi-
ological or physical properties and their preparation represents an
important field of research in organic chemistry.1 In recent years, the
palladium-catalyzed direct arylation of heteroaromatics has emerged
as a very powerful tool for the preparation of arylated hetero-
aromatics.2e5 However, there are still important limitations in terms
of heteroaromatics functional group tolerance for this coupling pro-
cedure. Directarylations of thiophenes substituted bynitrile, carbonyl,
ester, methylalcohol as the functional groups have been described.4f,6
On the other hand, the use of heteroaromatics bearing free NH2 sub-
stituents has attracted much less attention. To our knowledge, only
purine derivatives or pyrazoles bearing a free NH2 function have been
employed.7,8 Some protected amines have also been used.9e13
lectivity of the coupling with some thiophene derivatives bearing
unprotected amino functions was also studied.
2. Results and discussion
We decided to employ methyl 3-amino-4-methylthiophene-2-
carboxylate as the test substrate for our study. Carbon C2 of this
substrate is blocked by an ester, which can be easily removed. This
commercially available compound is a precursor of articaine
(Fig. 1), which is actually the most widely used local dental an-
aesthetic in several European countries.
However, the direct use of thiophenes bearing unprotected
functions, such as NH2 would be more useful in organic synthesis
since it would allow to avoid the protection/deprotection sequence,
and would provide a more environmentally and economically at-
tractive access to such arylated thiophenes. Therefore, the discov-
ery of effective conditions, for the direct coupling of such
thiophenes with aryl halides, would be a considerable advantage
for industrial applications and for sustainable development.
We have recently reported preliminary results on the direct
arylation of some thiophenes bearing a free NH2 substituent.14
Fig. 1. Articaine and its precursor.
First, we examined the influence of the base, solvent, catalyst
precursor and reaction temperature for the coupling of 4-
trifluoromethylbromobenzene with methyl 3-amino-4-methylthio
phene-2-carboxylate (Scheme 1, Table 1). In the course of this re-
action, several compounds were produced. However, the amination
* Corresponding author. E-mail address: henri.doucet@univ-rennes1.fr
(H. Doucet).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.053

7464
F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
of 150 ꢀC. At this temperature, in the presence of KOAc as the base,
DMAc as the solvent and PdCl(C3H5)(dppb) as the catalyst, 1a was
obtained in 82% yield (Table 1, entry 7).
Quite similar results were obtained in the presence of 1,2-
bis(diphenylphosphino)ethane (dppe) as the ligand; whereas, the
use of PPh3 led to a lower conversion of the aryl bromide (Table 1,
entries 16 and 17). The use of ethers, such as cyclopentyl methyl
ether (CPME) or di-n-butyl ether as solvents led selectively to 1a,
but moderate conversions of 4-trifluoromethylbromobenzene were
observed (Table 1, entries 11 and 12).
We also compared the reactivity of bromobenzene, chloroben-
zene, phenyltosylate and phenyltriflate using similar reaction
conditions (Scheme 2). As expected, no reaction was observed in
the presence of phenyltosylate and chlorobenzene. The oxidative
addition of such compounds to palladium is probably too slow
under these conditions. On the other hand, a moderate yield of 29%
in 2 was obtained with phenyltriflate. However, the highest yield
was obtained using bromobenzene.
Scheme 1.
Table 1
Influence of the reaction conditions on the selectivity for the arylation of methyl 3-
amino-4-methylthiophene-2-carboxylate with 4-(trifluoromethyl)bromobenzene
(Scheme 1)
Entry Solvent
Base
Catalyst
Temp Conv. Ratio
(ꢀC) (%)
1a/1b/1c/1e
1
2
3
4
5
6
7
8
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
NMP
K2CO3 PdCl(C3H5)(dppb)
Na2CO3 PdCl(C3H5)(dppb)
Cs2CO3 PdCl(C3H5)(dppb)
CsOAc PdCl(C3H5)(dppb)
NaOAc PdCl(C3H5)(dppb)
150
150
150
150
150
150
120
120
120
120
120
5
d
13 2:0:1:8
11 2:1:4:0
98 43:37:12:2
43 28:5:5:4
100 19:66:11:3
100 93:3:1:1a
100 84:2:3:10
93 84:4:0:5
63 58:0:0:5
46 41:0:0:0:4b
KOAc
KOAc
KOAc
KOAc
KOAc
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
Scheme 2.
9
10
11
DMF
Toluene
Di-n-butyl KOAc
Then, the scope of the coupling of methyl 3-amino-4-
methylthiophene-2-carboxylate with a set of para-, meta-, or or-
tho-substituted aryl bromides and also with heteroaryl bromides
was investigated (Scheme 3, Tables 2e5).
ether
12
13
14
15
16
17
CPME
DMAc
DMAc
DMAc
DMAc
DMAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
PdCl(C3H5)(dppb)
Pd(OAc)2
Pd(OAc)2/dppb
½ [PdCl(C3H5)]2
½ [PdCl(C3H5)]2/dppe 120
½ [PdCl(C3H5)]2/2 PPh3 120
120
120
120
120
52 37:0:0:0:3b,c
100 78:15:6:1
92 83:1:0:8
100 78:0:6:9
100 92:1:1:6
83 75:2:0:5
d
Conditions: [Pd] (0.02 equiv), 4-(trifluoromethyl)bromobenzene (1 equiv), methyl
3-amino-4-methylthiophene-2-carboxylate (2 equiv), base (2 equiv), 20 h. Con-
version of 4-(trifluoromethyl)bromobenzene. Traces of 4-(trifluoromethyl)benzene
were also observed in some cases.
Scheme 3.
a
Compound 1a was isolated in 82% yield.
Reaction time: 48 h.
CPME: cyclopentyl methyl ether, 13% of debromation was observed.
Pd(OAc)2 (0.01 equiv).
The reactionsperformed with para-substitutedelectron-deficient
aryl bromides and 2 mol % PdCl(C3H5)(dppb) as the catalyst proceed
conveniently in most cases (Table 2). Selective 5-arylations were
observed using 4-bromobenzaldehyde, 4-bromoacetophenone, 4-
bromopropiophenone, methyl 4-bromobenzoate, 4-bromobenzo
nitrile, 4-bromonitrobenzene or 4-bromofluorobenzene, resulting
in 74e90% yields of the products 3e10 (Table 2, entries 1e12). It
should be noted that even 4-chlorobromobenzene could be
employed to give 11 in 84% yield (Table 2, entry 13). In the course of
this reaction, no cleavage of the CeCl bond was observed, allowing
further transformations. Even the electron-rich aryl bromides 4-
bromotoluene or 4-tert-butylbromobenzene gave the desired cou-
plingproducts12 and13 ingoodyields(Table2, entries14and15). On
the other hand, 4-bromoanisole gave 14 in a lower yield of 58% due to
a partial conversion; and the strongly deactivated aryl bromide, 4-
bromo-N,N-dimethylaniline was recovered unreacted (Table 2, en-
tries 16 and 17).
b
c
d
product 1f was not detected. On the other hand, the 2,5-diarylated
product 1b and the decarboxylated product 1c were obtained in rel-
atively high yields in some cases. We initially examined the influence
of the nature of the base on the product distribution for this reaction
using DMAc as the solvent. DMAc is known to be a suitable solvent for
direct arylations of heteroaromatics.2 K2CO3, Na2CO3 or Cs2CO3 gave
poor conversions of 4-(trifluoromethyl)bromobenzene, and target
compound 1a was obtained only in traces (Table 1, entries 1e3). The
use of acetates as the base gave better results and the desired com-
pound 1a was obtained in 19e43% selectivity together with moderate
to large amounts of 1b and 1c (Table 1, entries 4e6). It should be noted
that the inter- or intramolecular palladium-catalyzed amination of
some 3-aminothiophenes with aryl bromides have been described
using Cs2CO3 or K3PO4 as the bases in toluene.15 Interestingly, acetates
appear to be not suitableto catalyze amination reaction, asnot trace of
1f was detected. The good performance of acetates as the base for
direct arylation is consistent with a concerted metallation deproto-
nation (CMD) pathway.16 Then, in order to reduce the amount of
decarboxylated products, we performed the reaction at 120 ꢀC instead
As the use of 1 mol % of the phosphine-free catalyst Pd(OAc)2 has
alsobeen found to promote efficiently the direct arylation of methyl 3-
amino-4-methylthiophene-2-carboxylate in the presence of 4-(tri-
fluoromethyl)bromobenzene (Table 1, entry 13); this air stable and
easily available catalyst was also evaluated with a few other aryl bro-
mides. Good yields in 4,
8 and 9 were obtained with 4-
bromoacetophenone, 4-bromobenzonitrile and 4-bromonitroben

F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
7465
Table 2
Table 3
Direct arylation of methyl 3-amino-4-methylthiophene-2-carboxylate with para-
Direct arylation of methyl 3-amino-4-methylthiophene-2-carboxylate with meta-
substituted aryl bromides (Scheme 3)
substituted aryl bromides (Scheme 3)
Entry
Aryl bromide
Product
Yield (%)
Entry
1
Aryl halide
OHC
Product
Yield (%)
83
NH2
OHC
MeOC
NC
Br
1
2
3
4
5
87
44a
90
CO2Me
S
3
16
NH2
MeOC
NC
Br
2
74
CO2Me
S
17
4
91a
86
NH2
CO2Me
Br
3
4
5
6
7
90
45a
92
S
18
5
NH2
CO2Me
NH2
F3C
F3C
Br
Br
Br
6
7
74
74
CO2Me
S
PhOC
S
PhOC
19
6
43a
79
NH2
NH2
CO2Me
O2N
Cl
O2N
Cl
CO2Me
S
S
S
MeO2C
7
20
NH2
Br
8
87
70a
83
8
74
80
70
69
CO2Me
NH2
8
21
9
Br
9
10
11
12
CO2Me
NH2
S
22
9
78a
89
Br
10
11
MeO
CO2Me
S
MeO
23
10
NH2
NH2
H2N
H2N
I
Br
13
84
CO2Me
S
CO2Me
Cl
S
24
Cl
11
12
13
NH2
Cl
Cl
I
12
13
51
42
14
15
81
67
CO2Me
S
H2N
H2N
25
NH2
EtO2C
H2N
NH2
CO2Me
EtO2C
H2N
I
CO2Me
S
S
26
tBu
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-amino-
4-methylthiophene-2-carboxylate (2 equiv), KOAc (2 equiv), DMAc, 20 h, 120 ꢀC.
16
17
58
0
a
Pd(OAc)2 (0.01 equiv).
14
15
Br
zene and 1 mol % Pd(OAc)2 (Table 2, entries 4, 9 and 11). On the other
hand, a moderate conversion of 4-bromobenzaldehyde and a low yield
of 44% in 3 was obtained using this catalyst (Table 2, entry 2).
Me2N
As expected, the reactivity of the meta-substituted aryl bro-
mides is similar to the reactivity of the para-substituted. The use of
electron-deficient aryl bromides, such as 3-bromobenzaldehyde,
3-bromobenzonitrile, 3-(trifluoromethyl)bromobenzene or 3-
bromonitrobenzene gave 16e20 in very high yields (Table 3,
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-amino-
4-methylthiophene-2-carboxylate (2 equiv), KOAc (2 equiv), DMAc, 20 h, 120 ꢀC.
a
Pd(OAc)2 (0.01 equiv).

7466
F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
Table 4
entries 1e3, 5 and 6). 2-Bromonaphthalene or 6-methoxy-2-
bromonaphthalene also led to the desired coupling products 22
and 23 in good yields (Table 3, entries 9 and 10). The arylation of
methyl 3-amino-4-methylthiophene-2-carboxylate with un-
protected iodoanilines also proceeds using the same reaction con-
ditions. From 3-iodoaniline, 24 was obtained in 69% yield (Table 3,
entry 11). Functionalized iodoanilines gave the arylation products
25 and 26 in moderate yields (Table 3, entries 12 and 13). It should
be noted that, with 3-bromoaniline, no formation of product 24 was
detected.
Then, the reactivity of a set of ortho-substituted aryl bromides
was studied (Table 4). Electron-deficient and quite congested sub-
strates, such as methyl 2-bromobenzoate, 2-bromobenzonitrile or
2-trifluoromethylbromobenzene were also found to be reactive
under these reaction conditions and gave 27e29 in 87e90% yields
(Table 4, entries 1, 2 and 4). On the other hand, in the presence of 2-
bromobenzaldehyde, no formation of 30 was detected (Table 4,
entry 6). With this substrate, the formation of several unidentified
products was observed. The coupling with 1-bromonaphthalene
proceed to give 31 in 65% yield (Table 4, entry 7). Finally, the ste-
rically very congested substrate, 9-bromonaphthalene was
employed and the target compound 32 was obtained in 51% yield
(Table 4, entry 8).
Direct arylation of methyl 3-amino-4-methylthiophene-2-carboxylate with ortho-
substituted aryl bromides (Scheme 3)
Entry
1
Aryl bromide
Product
NH2
Yield (%)
87
CO2Me
Br
MeO2C
NC
CO2Me
S
27
NH2
CO2Me
CN
Br
2
3
4
5
6
90
38a
88
S
28
NH2
CO2Me
CF3
Br
F3C
S
S
29
30
30a
0
NH2
CHO
Br
OHC
CO2Me
NH2
Pyridines are probably the most common heterocyclic motif
found in pharmaceutically active compounds. Therefore, pre-
parative methods of biheteroaryl derivatives containing pyridines
remain an essential research topic in organic synthesis. We ob-
served that the coupling of 3- or 4-bromopyridines, with methyl 3-
7
8
65
51
CO2Me
S
31
NH2
CO2Me
amino-4-methylthiophene-2-carboxylate
using
2
mol
%
Br
PdCl(C3H5)(dppb) as the catalyst proceed nicely to give 33 and 34 in
good yields (Table 5, entries 1 and 3). On the other hand, the use of
3-chloropyridine as coupling partner gave no product 33 (Table 5,
entry 2). The reactivity of 5-bromopyrimidine and 3-
bromoquinoline was also examined, and the desired coupling
products 34 and 36 were obtained in 76% and 70% yields, re-
spectively (Table 5, entries 4 and 5).
S
32
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-amino-
4-methylthiophene-2-carboxylate (2 equiv), KOAc (2 equiv), DMAc, 20 h, 120 ꢀC.
a
Pd(OAc)2 (0.01 equiv).
As the decarboxylation of methyl 3-amino-4-methylthiophene-
2-carboxylate in the presence of a relatively strong base is quite
easy, we examined the reactivity of this substrate using a mixture of
KOH and KOAc as the bases (Scheme 4, Table 6). Using these con-
ditions, in the presence of 3-bromopyridine or 4-bromotoluene as
the coupling partners, only the 2-arylated products 37b and 38b
were isolated. No formation of the other regioisomers or diarylated
thiophenes was detected.
Table 5
Direct arylation of methyl 3-amino-4-methylthiophene-2-carboxylate with heter-
oaryl bromides (Scheme 3)
Entry
Aryl bromide
Product
Yield (%)
1
77
33
33
34
35
Cl
2
0
N
Scheme 4.
3
4
5
89a
76
We also performed a 2,5-diarylation reaction using 2 equiv of
the aryl bromide, 1 equiv of the thiophene derivative and a mixture
of KOH and KOAc as the base (Table 6, entry 3). The target 2,5-
diarylated product 1b was obtained in 70% yield.
It should be noted that products 1c or 37a could be obtained in
good yields by decarboxylation of 1a or 33 using basic conditions
(Scheme 5). Therefore, the presence of the ester substituents at
carbon C2 of thiophene appears to be useful to block this reactive
carbon and to provide alternative regioisomeric arylthiophenes.
Then, we examined the reactivity of 3-amino-4-
methylthiophene (Scheme 6, Table 7). As expected, the direct ary-
lation of this substrate with 4-(trifluoromethyl)bromobenzene
gave regioselectively the C2 arylated product 1d (Table 7, entry 1).
NH2
CO2Me
N
S
N
70
36
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-amino-
4-methylthiophene-2-carboxylate (2 equiv), KOAc (2 equiv), DMAc, 20 h, 120 ꢀC.
a
KOAc (3 equiv).

F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
7467
Table 6
Table 7
Direct arylation of methyl 3-amino-4-methylthiophene-2-carboxylate in the pres-
ence of KOH (Scheme 4)
Direct arylation of 3-amino-4-methylthiophene (Scheme 6)
Entry
1
Aryl bromide
Product
Yield (%)
Entry
Aryl bromide
Product
Yield (%)
77
85
1
66
1d
39
37b
NH2
2
S
2
3
64
CN
38b
3
4
79
62
70a
38b
40
1b
NH2
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-amino-
4-methylthiophene-2-carboxylate (2 equiv), KOAc (1.5 equiv), KOH (1.5 equiv),
DMAc, 20 h, 150 ꢀC.
S
OMe
a
Aryl bromide (2 equiv), methyl 3-amino-4-methylthiophene-2-carboxylate
(1 equiv).
5
78
37b
NH2
CN
6
7
83
80
S
41
NH2
S
S
Scheme 5.
NC
NH2
42
8
75
43
Scheme 6.
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), 3-amino-4-
methylthiophene (2 equiv), KOAc (2 equiv), DMAc, 20 h, 150 ꢀC.
This high regioselectivity in favour of the arylation at carbon C2
might be due either to the coordination of the amino substituent to
palladium or from electronic factors. Several other aryl bromides
were coupled with 3-amino-4-methylthiophene, and both
electron-deficient and electron-rich aryl bromides, such as 2-, 3- or
4-bromobenzonitriles or 4-bromoanisole gave the C2 arylated
thiophene 39e42 in good yields (Table 7, entries 2, 4, 6 and 7).
The synthesis of a wide variety of 2,5-diarylated thiophenes
bearing a free NH2 substituent at C3 is also possible. Moreover, this
method allows to introduce the aryls at C2 or C5 in any order.
Therefore, it is possible to choose the most suitable sequence of
reactions in order to obtain the highest yield. For example, com-
pound 37a reacted with 4-bromotoluene gave 44 in 75% yield
(Scheme 7, top); whereas, the reaction of 38b with 3-
bromopyridine led to 44 in only 40% yield (Scheme 7, bottom).
As the amino substituent on thiophenes appears to have a very
strong directing effect in the course of direct arylation reactions,
the regioselectivity of the coupling with methyl 3-
aminothiophene-2-carboxylate was unpredictable. In the pres-
ence of 1-bromonaphthalene, we observed the formation of
a mixture of the 4- and 5-arylated products 47b and 47 in 12% and
52% yields, respectively (GC ratio 47/47b¼77:23) (Table 8, entry 3).
On the other hand, the reaction with the electron-deficient aryl
bromides, 4-bromopropiophenone or 3-bromobenzaldehyde and
with the congested aryl bromides 9-bromoanthracene gave the C5
arylated products 45, 46 and 48 in higher regioselectivities (Table 8,
entries 1, 2 and 4). In the presence of 9-bromoanthracene, the C4
Scheme 7.

7468
F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
Table 8
EtO2C
PdCl(C3H5)(dppb) 2%
Direct arylation of methyl 3-aminothiophene-2-carboxylate (Scheme 8)
+
Br
CN
H2N
Entry
1
Aryl bromide
Product
Yield (%)
51
S
KOAc, DMAc,
150 °C, 20 h
NH2
CO2Me
Br
Scheme 10.
EtOC
S
EtOC
OHC
45
NH2
CO2Me
3. Conclusions
OHC
Br
2
3
67
S
In summary, we have demonstrated that, when appropriate
reaction conditions are employed, the palladium-catalyzed direct
arylation at C2 or C5 of some free NH2 substituted thiophene
derivatives with aryl bromides proceed nicely. The choice of
KOAc as the base inhibits the amination reaction and promotes
the direct arylation. This result is consistent with a concerted
metallation deprotonation mechanism.16 A wide variety of sub-
stituents, such as propionyl, acetyl, formyl, benzoyl, ester, nitrile,
nitro, trifluoromethyl, fluoro, chloro or methoxy on the aryl
bromide are tolerated. To our knowledge, this is the first method
for direct arylation of free NH2 substituted thiophenes. The most
reactive carbon of 3-aminothiophenes appears to be the carbon
C2. However, the presence of an ester substituent at C2 was
found to be useful to block this highly reactive position to pro-
vide the 5-arylated thiophenes. This procedure is attractive as it
allows to prepare arylated heteroaromatics bearing free NH2
substituents without protection/deprotection sequence and
therefore should provide a ‘greener’ and more economic access
to such compounds.
46
NH2
CO2Me
52a
Br
S
47
NH2
CO2Me
Br
4
39b
S
48
Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1 equiv), methyl 3-
aminothiophene-2-carboxylate (2 equiv), KOAc (2 equiv), DMAc, 20 h, 120 ꢀC.
a
Product 47b corresponding to a C4 arylation was also isolated in 12%.
Product 48b corresponding to a C4 arylation was also isolated in 4%.
b
arylated product was obtained in only 4% yield, whereas the C5
arylated product 48 was isolated in 39% yield.
4. Experimental
4.1. General remarks
All reactions were performed in Schlenck tubes under argon.
DMAc analyticalgradewasnot distilledbeforeuse. Potassium acetate
99þ was used. Commercial aryl bromides and thiophene derivatives
were used without purification. 1H (300 MHz), 13C (75 MHz) spectra
were recorded in CDCl3 solutions. Chemical shifts are reported in
parts per million relative to CDCl3 (1H: 7.26 and 13C: 77.0). Flash
chromatography was performed on silica gel (230e400 mesh).
Scheme 8.
The arylation at C4 of 3-aminothiophenes is possible (see Table
8). Therefore, we examined the C4 arylation of two methyl 3-amino-
5-arylthiophene-2-carboxylates with aryl bromides (Scheme 9). The
desired coupling products 49 and 50 were obtained in moderate
yields due to a partial conversion of the aryl bromides.
4.2. Generalprocedureforthesynthesisofproducts1aand2e36
As a typical experiment, the reaction of 4-(trifluoromethyl)bro-
mobenzene (0.225 g,1 mmol), methyl 3-amino-4-methylthiophene-
2-carboxylate (0.342 g, 2 mmol) and KOAc (0.196 g, 2 mmol) at 120 ꢀC
during 20 h in DMAc (3 mL) in the presence of PdCl(C3H5)(dppb)
(12.2 mg, 0.02 mmol) under argon affords methyl 3-amino-4-
methyl-5-(4-trifluoromethylphenyl)-thiophene-2-carboxylate 1a
after extraction with dichloromethane, evaporation and filtration on
silica gel (pentane/ether) in 82% (0.258 g) yield.
R2
NH2
CO2Me
S
+
NH2
CO2Me
PdCl(C3H5)(dppb) 2%
KOAc, DMAc,
120 °C, 20 h
R1
R1
Br
R2
S
4.2.1. 4-Methyl-2,5-bis-(4-trifluoromethylphenyl)-thiophen-3-
ylamine (1b). 4-(Trifluoromethyl)bromobenzene (0.225 g,1 mmol),
methyl 3-amino-4-methylthiophene-2-carboxylate (0.171 g,
1 mmol), KOH (0.084, 1.5 mmol) and KOAc (0.147 g, 1.5 mmol) in the
presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) in DMAc at
150 ꢀC during 20 h affords 1b in 70% (0.281 g) yield.
R1
H
R2
CF3
Product Yield (%)
49
48
45
tBu COMe 50
Scheme 9.
Then, we examined the influence of the substituents distribution
on the thiophene ring. A permutation of the amino and ester sub-
stituents was found to drastically modify the thiophene reactivity.
No formation of coupling products was detected in the presence of
4-bromobenzonitrile using similar reaction conditions (Scheme 10).
4.2.2. 4-Methyl-5-(4-trifluoromethylphenyl)-thiophen-3-ylamine
(1c). Methyl 3-amino-4-methyl-5-(4-trifluoromethylphenyl)-thio-
phene-2-carboxylate 1a (0.315 g, 1 mmol) and KOH (0.067 g,
1.2 mmol) were stirred at 100 ꢀC during 15 h in a mixture EtOH/H2O
(3/1 mL). After addition of an HCl solution to reach pH 7, the

F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
7469
solution was washed with saturated aq NaHCO3. After extraction
with dichloromethane, evaporation and filtration on silica gel, 1c
was obtained in 78% (0.201 g) yield.
methylthiophene-2-carboxylate (0.342 g, 2 mmol) affords 12 in
81% (0.212 g) yield.
4.2.16. Methyl 3-amino-5-(4-tert-butylphenyl)-4-methylthiophene-
2-carboxylate (13). 4-tert-Butylbromobenzene (0.213 g, 1 mmol)
and methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 13 in 67% (0.203 g) yield.
4.2.3. 4-Methyl-2-(4-trifluoromethylphenyl)-thiophen-3-ylamine
(1d). 4-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol), 3-
amino-4-methylthiophene (0.228 g, 2 mmol) and KOAc (0.196 g,
2 mmol) at 150 ꢀC during 20 h in DMAc (3 mL) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon affords 1d in
77% (0.198 g) yield.
4.2.17. Methyl 3-amino-5-(4-methoxyphenyl)-4-methyl-thiophene-
2-carboxylate (14). 4-Bromoanisole (0.187 g, 1 mmol) and methyl
3-amino-4-methylthiophene-2-carboxylate (0.342 g, 2 mmol) af-
fords 14 in 58% (0.161 g) yield.
4.2.4. 4,40-Bis-(trifluoromethyl)biphenyl (1e). This side-product was
detected using GC/MS.
4.2.18. Methyl 3-amino-5-(3-formylphenyl)-4-methylthiophene-2-
carboxylate (16). 3-Bromobenzaldehyde (0.185 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 16 in 83% (0.228 g) yield.
4.2.5. Methyl 3-amino-4-methyl-5-phenylthiophene-2-carboxylate
(2).17 Bromobenzene (0.157 g, 1 mmol) and methyl 3-amino-4-
methylthiophene-2-carboxylate (0.342 g, 2 mmol) affords 2 in
66% (0.163 g) yield.
4.2.19. 5-(3-Acetylphenyl)-3-amino-4-methyl-thiophene-2-
carboxylic acid methyl ester (17). 3-Bromoacetophenone (0.199 g,
1 mmol) and methyl 3-amino-4-methylthiophene-2-carboxylate
(0.342 g, 2 mmol) affords 17 in 74% (0.214 g) yield.
4.2.6. Methyl 3-amino-5-(4-formylphenyl)-4-methylthiophene-2-
carboxylate (3). 4-Bromobenzaldehyde (0.185 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 3 in 87% (0.239 g) yield.
4.2.20. Methyl 3-amino-5-(3-cyanophenyl)-4-methylthiophene-2-
carboxylate (18). 3-Bromobenzonitrile (0.182 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 18 in 90% (0.245 g) yield.
4.2.7. Methyl 5-(4-acetylphenyl)-3-amino-4-methylthiophene-2-
carboxylate (4). 4-Bromoacetophenone (0.199 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 4 in 90% (0.260 g) yield.
4.2.21. Methyl 3-amino-4-methyl-5-(3-trifluoromethylphenyl)-thio-
4.2.8. Methyl 3-amino-4-methyl-5-(4-propionylphenyl)-thiophene-
2-carboxylate (5). 4-Bromopropiophenone (0.213 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 5 in 86% (0.261 g) yield.
phene-2-carboxylate
(0.225 g, 1 mmol) and methyl 3-amino-4-methylthiophene-2-
carboxylate (0.342 g, 2 mmol) affords 19 in 92% (0.290 g) yield.
(19). 3-(Trifluoromethyl)bromobenzene
4.2.22. 3-Amino-4-methyl-5-(3-nitrophenyl)-thiophene-2-carboxylic
acid methyl ester (20). 3-Bromonitrobenzene (0.202 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 20 in 79% (0.231 g) yield.
4.2.9. 3-Amino-5-(4-benzoylphenyl)-4-methyl-thiophene-2-
carboxylic acid methyl ester (6). 4-Bromobenzophenone (0.261 g,
1 mmol) and methyl 3-amino-4-methylthiophene-2-carboxylate
(0.342 g, 2 mmol) affords 6 in 74% (0.260 g) yield.
4.2.23. 3-Amino-5-(3-chlorophenyl)-4-methyl-thiophene-2-
carboxylic acid methyl ester (21). 3-Bromochlorobenzene (0.192 g,
1 mmol) and methyl 3-amino-4-methylthiophene-2-carboxylate
(0.342 g, 2 mmol) affords 21 in 84% (0.208 g) yield.
4.2.10. Methyl 3-amino-5-[4-(methoxycarbonyl)phenyl]-4-
methylthiophene-2-carboxylate
(7). Methyl
4-bromobenzoate
(0.215 g, 1 mmol) and methyl 3-amino-4-methylthiophene-2-
carboxylate (0.342 g, 2 mmol) affords 7 in 74% (0.226 g) yield.
4.2.24. Methyl 3-amino-4-methyl-5-naphthalen-2-ylthiophene-2-
carboxylate (22). 2-Bromonaphthalene (0.207 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 22 in 80% (0.238 g) yield.
4.2.11. Methyl 3-amino-5-(4-cyanophenyl)-4-methylthiophene-2-
carboxylate (8). 4-Bromobenzonitrile (0.182 g,
1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 8 in 87% (0.237 g) yield.
4.2.25. 3-Amino-5-(6-methoxynaphthalen-2-yl)-4-methyl-thio-
4.2.12. Methyl 3-amino-4-methyl-5-(4-nitrophenyl)-thiophene-2-
carboxylate (9). 4-Bromonitrobenzene (0.202 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 9 in 83% (0.242 g) yield.
phene-2-carboxylic
acid
methyl
ester
(23). 2-Bromo-6-
methoxynaphthalene (0.237 g, 1 mmol) and methyl 3-amino-4-
methylthiophene-2-carboxylate (0.342 g, 2 mmol) affords 23 in
70% (0.229 g) yield.
4.2.13. Methyl 3-amino-5-(4-fluorophenyl)-4-methylthiophene-2-
carboxylate (10). 4-Bromofluorobenzene (0.175 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 10 in 89% (0.236 g) yield.
4.2.26. 3-Amino-5-(3-aminophenyl)-4-methyl-thiophene-2-
carboxylic acid methyl ester (24). 3-Iodoaniline (0.219 g, 1 mmol)
and methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 24 in 69% (0.181 g) yield.
4.2.14. Methyl 3-amino-5-(4-chlorophenyl)-4-methylthiophene-2-
carboxylate (11). 4-Bromochlorobenzene (0.192 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 11 in 84% (0.236 g) yield.
4.2.27. 3-Amino-5-(4-amino-3-chlorophenyl)-4-methyl-thiophene-
2-carboxylic acid methyl ester (25). 2-Chloro-4-iodoaniline
(0.253 g, 1 mmol) and methyl 3-amino-4-methylthiophene-2-
carboxylate (0.342 g, 2 mmol) affords 25 in 51% (0.151 g) yield.
4.2.15. Methyl 3-amino-4-methyl-5-p-tolylthiophene-2-carboxylate
4.2.28. 3-Amino-5-(4-amino-3-ethoxycarbonyl-phenyl)-4-methyl-
(12). 4-Bromotoluene (0.171 g, 1 mmol) and methyl 3-amino-4-
thiophene-2-carboxylic acid methyl ester (26). Ethyl 2-amino-5-

7470
F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
iodobenzoate (0.291 g,
methylthiophene-2-carboxylate (0.342 g, 2 mmol) affords 26 in
42% (0.140 g) yield.
1
mmol) and methyl 3-amino-4-
(0.248 g, 1 mmol) and KOH (0.067 g, 1.2 mmol) were stirred at
100 ꢀC during 15 h in a mixture EtOH/H2O (3/1 mL). After addition
of an HCl solution to reach pH 7, the solution was washed with
saturated aq NaHCO3. After extraction with dichloromethane,
evaporation and filtration on silica gel, 37a was obtained in 75%
(0.142 g) yield.
4.2.29. Methyl 3-amino-5-(2-methoxycarbonylphenyl)-4-
methylthiophene-2-carboxylate (27). Methyl 2-bromobenzoate
(0.215 g, 1 mmol) and methyl 3-amino-4-methylthiophene-2-
carboxylate (0.342 g, 2 mmol) affords 27 in 87% (0.266 g) yield.
4.2.41. 4-(3-Amino-4-methylthiophen-2-yl)benzonitrile
Bromobenzonitrile (0.182 g, mmol),
(39). 4-
3-amino-4-
1
4.2.30. Methyl 3-amino-5-(2-cyanophenyl)-4-methylthiophene-2-
carboxylate (28). 2-Bromobenzonitrile (0.182 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 28 in 90% (0.245 g) yield.
methylthiophene (0.226 g, 2 mmol) and KOAc (0.196 g, 2.0 mmol)
at 150 ꢀC during 20 h in DMAc (3 mL) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) affords 39 in 85% (0.182 g)
yield.
4.2.31. 3-Amino-4-methyl-5-(2-trifluoromethylphenyl)-thiophene-2-
carboxylate (29). 2-(Trifluoromethyl)bromobenzene (0.225 g,
1 mmol) and methyl 3-amino-4-methylthiophene-2-carboxylate
(0.342 g, 2 mmol) affords 29 in 88% (0.277 g) yield.
4.2.42. 2-(4-Methoxyphenyl)-4-methylthiophen-3-amine
(40). 4-
Bromoanisole (0.187 g, 1 mmol), 3-amino-4-methylthiophene
(0.226 g, 2 mmol) and KOAc (0.196 g, 2.0 mmol) at 150 ꢀC during
20 h in DMAc (3 mL) in the presence of PdCl(C3H5)(dppb) (12.2 mg,
0.02 mmol) affords 40 in 62% (0.136 g) yield.
4.2.32. Methyl 3-amino-4-methyl-5-naphthalen-1-ylthiophene-2-
carboxylate (31). 1-Bromonaphthalene (0.207 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 31 in 65% (0.193 g) yield.
4.2.43. 3-(3-Amino-4-methylthiophen-2-yl)benzonitrile
Bromobenzonitrile (0.182 g, mmol),
methylthiophene (0.226 g, 2 mmol) and KOAc (0.196 g, 2.0 mmol)
at 150 ꢀC during 20 h in DMAc (3 mL) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) affords 41 in 83% (0.178 g)
yield.
(41). 3-
3-amino-4-
1
4.2.33. Methyl 3-amino-5-anthracen-9-yl-4-methylthiophene-2-
carboxylate (32). 9-Bromoanthracene (0.257 g, 1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
2 mmol) affords 32 in 51% (0.177 g) yield.
4.2.44. 2-(3-Amino-4-methylthiophen-2-yl)benzonitrile (42). 2-Bro
mobenzonitrile (0.182 g, 1 mmol), 3-amino-4-methylthiophene
(0.226 g, 2 mmol) and KOAc (0.196 g, 2.0 mmol) at 150 ꢀC during
20 h in DMAc (3 mL) in the presence of PdCl(C3H5)(dppb) (12.2 mg,
0.02 mmol) affords 42 in 80% (0.171 g) yield.
4.2.34. Methyl 3-amino-4-methyl-5-pyridin-3-ylthiophene-2-
carboxylate (33). 3-Bromopyridine (0.158 g, 1 mmol) and methyl
3-amino-4-methylthiophene-2-carboxylate (0.342 g, 2 mmol) af-
fords 33 in 77% (0.191 g) yield.
4.2.45. 4-Methyl-2-(naphthalen-1-yl)thiophen-3-amine
Bromonaphthalene (0.207 g, mmol),
(43). 1-
3-amino-4-
4.2.35. Methyl 3-amino-4-methyl-5-pyridin-4-ylthiophene-2-
1
carboxylate (34). 4-Bromopyridine hydrochloride (0.194 g,
methylthiophene (0.226 g, 2 mmol) and KOAc (0.196 g, 2.0 mmol)
at 150 ꢀC during 20 h in DMAc (3 mL) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) affords 43 in 75% (0.179 g)
yield.
1
mmol), methyl 3-amino-4-methylthiophene-2-carboxylate
(0.342 g, 2 mmol) and KOAc (0.294 g, 3 mmol) affords 34 in 89%
(0.221 g) yield.
4.2.36. Methyl 3-amino-4-methyl-5-(pyrimidin-5-yl)thiophene-2-
4.2.46. 4-Methyl-5-pyridin-3-yl-2-p-tolylthiophen-3-ylamine
(44). 4-Bromotoluene (0.171 g, 1 mmol), 4-methyl-5-pyridin-3-
ylthiophen-3-ylamine 37a (0.380 g, 2 mmol) and KOAc (0.196 g,
2 mmol) at 150 ꢀC during 20 h in DMAc (3 mL) in the presence of
PdCl(C3H5)(dppb) (30.5 mg, 0.05 mmol) affords 44 in 75% (0.210 g)
yield.
carboxylate (35). 5-Bromopyrimidine (0.159 g,
1 mmol) and
methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g,
3 mmol) affords 35 in 76% (0.189 g) yield.
4.2.37. Methyl 3-amino-4-methyl-5-quinolin-3-ylthiophene-2-
carboxylate (36). 3-Bromoquinoline (0.208 g, 1 mmol) and methyl
3-amino-4-methylthiophene-2-carboxylate (0.342 g, 2 mmol) af-
fords 36 in 70% (0.209 g) yield.
4.2.47. Methyl 3-amino-5-(4-propionylphenyl)thiophene-2-
carboxylate (45). 4-Bromopropiophenone (0.213 g,
1 mmol),
methyl 3-aminothiophene-2-carboxylate (0.314 g, 2 mmol) and
KOAc (0.196 g, 2.0 mmol) at 120 ꢀC during 20 h in DMAc (3 mL) in
the presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under ar-
gon affords 45 in 51% (0.147 g) yield.
4.2.38. 4-Methyl-2-pyridin-3-ylthiophen-3-ylamine
(37b). 3-
Bromopyridine (0.158 g, mmol), methyl 3-amino-4-
1
methylthiophene-2-carboxylate (0.342 g, 2 mmol), KOH (0.084,
1.5 mmol) and KOAc (0.147 g, 1.5 mmol) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) in DMAc at 150 ꢀC during
20 h affords 37b in 66% (0.125 g) yield.
4.2.48. Methyl 3-amino-5-(3-formylphenyl)thiophene-2-carboxylate
(46). 3-Bromobenzaldehyde (0.185 g,
aminothiophene-2-carboxylate (0.314 g,
1
mmol), methyl 3-
2 mmol) and KOAc
4.2.39. 4-Methyl-2-p-tolylthiophen-3-ylamine
(38b). 4-
(0.196 g, 2.0 mmol) at 120 ꢀC during 20 h in DMAc (3 mL) in the
presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon
affords 46 in 67% (0.175 g) yield.
Bromotoluene (0.171 g, mmol), methyl 3-amino-4-
1
methylthiophene-2-carboxylate (0.342 g, 2 mmol), KOH (0.084,
1.5 mmol) and KOAc (0.147 g, 1.5 mmol) in the presence of
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) in DMAc at 150 ꢀC during
20 h affords 38b in 64% (0.130 g) yield.
4.2.49. Methyl 3-amino-5-naphthalen-1-yl-thiophene-2-carboxylate
(47) and methyl 3-amino-4-naphthalen-1-yl-thiophene-2-
carboxylate (47b). 1-Bromonaphthalene (0.207 g,
1
mmol),
4.2.40. 4-Methyl-5-pyridin-3-ylthiophen-3-ylamine (37a). Methyl
methyl 3-aminothiophene-2-carboxylate (0.314 g, 2 mmol) and
KOAc (0.196 g, 2 mmol) in the presence of PdCl(C3H5)(dppb)
3-amino-4-methyl-5-pyridin-3-ylthiophene-2-carboxylate
33

F. Derridj et al. / Tetrahedron 68 (2012) 7463e7471
7471
(12.2 mg, 0.02 mmol) in DMAc at 120 ꢀC during 20 h affords the
products 47 in 52% (0.147 g) and 47b in 12% (0.034 g) yields.
ꢀ
1832e1846; (b) Smaliy, R. V.; Beauperin, M.; Cattey, H.; Meunier, P.; Hierso, J.-
C.; Roger, J.; Doucet, H.; Coppel, Y. Organometallics 2009, 28, 3152e3160; (c)
Roger, J.; Doucet, H. Adv. Synth. Catal. 2009, 351, 1977e1990; (d) Fall, Y.; Rey-
naud, C.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2009, 4041e4050; (e) Dong, J.
J.; Roger, J.; Verrier, C.; Martin, T.; Le Goff, R.; Hoarau, C.; Doucet, H. Green Chem.
4.2.50. Methyl 3-amino-5-(anthracen-9-yl)thiophene-2-carboxylate
(48) and methyl 3-amino-4-(anthracen-9-yl)thiophene-2-
carboxylate (48b). 9-Bromoanthracene (0.257 g, 1 mmol), methyl
3-aminothiophene-2-carboxylate (0.314 g, 2 mmol) and KOAc
(0.196 g, 2.0 mmol) at 120 ꢀC during 20 h in DMAc (3 mL) in the
presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon
ꢂ
2010, 12, 2053e2063; (f) Pozgan, F.; Roger, J.; Doucet, H. Adv. Synth. Catal. 2010,
352, 696e710; (g) Beydoun, K.; Zaarour, M.; Williams, J. A. G.; Doucet, H.;
Guerchais, V. Chem. Commun. 2012, 1260e1262.
5. For recent examples of direct arylations of thiophenes: (a) David, E.; Pellet-
Rostaing, S.; Lemaire, M. Tetrahedron 2007, 63, 8999e9006; (b) Amaladass, P.;
Clement, J. A.; Mohanakrishnan, A. K. Tetrahedron 2007, 63, 10363e10371; (c)
Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1851e1854; (d)
Bheeter, C. B.; Bera, J. K.; Doucet, H. J. Org. Chem. 2011, 76, 6407e6413; (e)
Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 2471e2473; (f)
Tanaka, S.; Tamba, S.; Tanaka, D.; Sugie, A.; Mori, A. J. Am. Chem. Soc. 2011, 133,
9700e9703; (g) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011, 76,
8138e8142; (h) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem.,
Int. Ed. 2010, 49, 8946e8949.
6. For examples of palladium-catalysed direct arylations using thiophenes bearing
formyl-, acetyl-, nitrile-, silyl, halo- or methylalcohol substituents: (a) Pivsa-Art,
S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
467e473; (b) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.; Lemaire, M. J.
Organomet. Chem. 1998, 567, 49e55; (c) Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286e5287; (d) Hassan, J.; Gozzi, C.;
Schulz, E.; Lemaire, M. J. Organomet. Chem. 2003, 687, 280e283; (e) Masui, K.;
Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074e5075; (f) Kobayashi, K.;
Sugie, A.; Takahashi, M.; Masui, K.; Mori, A. Org. Lett. 2005, 7, 5083e5085; (g)
Kobayashi, K.; Mohamed Ahmed, M. S.; Mori, A. Tetrahedron 2006, 62,
affords
methyl
3-amino-5-(anthracen-9-yl)thiophene-2-
carboxylate 48 in 39% (0.130 g) and 48b in 4% (0.013 g) yields.
4.2.51. Methyl 3-amino-5-phenyl-4-[4-(trifluoromethyl)phenyl]thio-
phene-2-carboxylate
(0.225 g, mmol), methyl 3-amino-5-phenylthiophene-2-
carboxylate (0.466 g, 2 mmol) and KOAc (0.196 g, 2 mmol) at
120 ꢀC during 20
in DMAc (3 mL) in the presence of
(49). 4-(Trifluoromethyl)bromobenzene
1
h
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon affords 49 in
48% (0.181 g) yield.
4.2.52. Methyl 4-(4-acetylphenyl)-3-amino-5-(4-tert-butylphenyl)
thiophene-2-carboxylate (50). 4-Bromoacetophenone (0.199 g,
ꢀ
9548e9553; (h) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J.
Org. Chem. 2009, 74, 1826e1834; (i) Dong, J. J.; Roger, J.; Doucet, H. Tetrahedron
Lett. 2009, 50, 2778e2781; (j) Liegault, B.; Petrov, I.; Gorlesky, S. I.; Fagnou, K. J.
1
mmol), methyl 3-amino-5-(4-tert-butylphenyl)thiophene-2-
carboxylate (0.578 g, 2 mmol) and KOAc (0.196 g, 2 mmol) at
120 ꢀC during 20
in DMAc (3 mL) in the presence of
ꢀ
Org. Chem. 2010, 75, 1047e1060; (k) Rene, O.; Fagnou, K. Org. Lett. 2010, 12,
2116e2119; (l) Beydoun, K.; Doucet, H. ChemSusChem 2011, 4, 526e534; (m)
Chen, L.; Roger, J.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. Chem. Commun. 2011,
1872e1874; (n) Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23, 1594e1600.
7. For examples of palladium-catalysed direct arylations using purine derivatives:
(a) Cerna, I.; Pohl, R.; Hocek, M. Chem. Commun. 2007, 4729e4730; (b) Storr, T.
E.; Firth, A. G.; Wilson, K.; Darley, K.; Baumann, C. G.; Fairlamb, I. J. S. Tetrahe-
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Org. Chem. 2008, 73, 9048e9054; (d) Storr, T. E.; Baumann, C. G.; Thatcher, R. J.;
De Ornellas, S.; Whitwood, A. C.; Fairlamb, I. J. S. J. Org. Chem. 2009, 74,
5810e5821; (e) Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. Org. Biomol.
Chem. 2009, 7, 4271e4278; (f) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. J.
Org. Chem. 2010, 75, 2302e2308; (g) Storr, T. E.; Strohmeier, J. A.; Baumann, C.
G.; Fairlamb, I. J. S. Chem. Commun. 2010, 6470e6472.
h
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon affords 50 in
45% (0.183 g) yield.
Acknowledgements
ꢁ
J.R. is grateful to ‘ Ministere de la Recherche’ for a grant. We
thank the CNRS and ‘ Rennes Metropole’ for providing financial
support, and PCAS SA for providing some aminothiophenes.
Supplementary data
8. For examples of palladium-catalysed direct arylations using free-(NH2) pyr-
azoles: Derridj, F.; Roger, J.; Djebbar, S.; Doucet, H. Adv. Synth. Catal. 2012, 354,
747e750.
9. For intramolecular cyclizations of aniline derivatives: Ackermann, L.; Altham-
mer, A.; Mayer, P. Synthesis 2009, 3493e3503.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.053.
10. For examples of palladium-catalysed direct arylations using protected 2-
aminothiazoles: (a) Priego, J.; Gutierrez, S.; Ferritto, R.; Broughton, H. B. Syn-
lett 2007, 2957e2960; (b) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9,
1449e1451.
11. For an example of palladium-catalysed intramolecular direct arylations using
a protected 2-aminofuran: Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem.
2001, 66, 1716e1724.
12. For examples of palladium-catalysed direct arylations using protected 2- or 3-
aminothiophenes: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola,
S. Synthesis 2008, 136e140; (b) Roger, J.; Doucet, H. Eur. J. Org. Chem. 2010,
4412e4425.
13. For an example of palladium-catalysed intramolecular direct arylation using an
aminothiophene derivative: Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G.
Tetrahedron 2003, 59, 3737e3743.
14. Derridj, F.; Roger, J.; Djebbar, S.; Doucet, H. Org. Lett. 2010, 12, 4320e4323.
15. (a) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. Tetrahedron 2006, 62,
11100e11105; (b) Carril, M.; SanMartin, R.; Dominguez, E.; Tellitu, I. Tetrahedron
2007, 63, 690e702.
16. (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127,
13754e13755; (b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118e1126.
17. Migianu, E.; Kirsch, G. Synthesis 2002, 1096e1100.
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ꢂ