Palladium-catalyzed direct arylation of free NH2-substituted thiophene derivatives

Article abstract of DOI:10.1021/ol101758w

Figure Presented. The palladium-catalyzed direct 2- or 5-arylation of some free NH₂-substituted thiophene derivatives was found to proceed in high yields using a variety of aryl bromides. In the course of these reactions, no coupling of the aryl bromide with the thiophene NH₂ substituent was detected. The presence of an ester substituent on C2 of thiophene was found to be useful to block this highly reactive carbon.

Full text of DOI:10.1021/ol101758w

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4320-4323
Palladium-Catalyzed Direct Arylation of
Free NH2-Substituted Thiophene
Derivatives
Fazia Derridj,† Julien Roger,‡ Safia Djebbar,† and Henri Doucet*,‡
Laboratoire d’Hydrome´tallurgie et Chimie Inorganique Mole´culaire, Faculte´ de
Chimie, U.S.THB Bab-Ezzouar, Alger, and Institut Sciences Chimiques de Rennes,
UMR 6226 CNRS-UniVersite´ de Rennes “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
henri.doucet@uniV-rennes1.fr
Received July 28, 2010
ABSTRACT
The palladium-catalyzed direct 2- or 5-arylation of some free NH2-substituted thiophene derivatives was found to proceed in high yields using
a variety of aryl bromides. In the course of these reactions, no coupling of the aryl bromide with the thiophene NH2 substituent was detected.
The presence of an ester substituent on C2 of thiophene was found to be useful to block this highly reactive carbon.
In recent years, the palladium-catalyzed direct arylation of
heteroaromatics has emerged as a very powerful method for
the preparation of arylated thiophenes.1-3 However, there
are still limitations for these reactions in terms of heteroaro-
matic functional group tolerance. If the presence of acetyl,
formyl, nitrile, and methylalcohol as the functional groups
on the thiophenes has been described,4 on the other hand,
the use of free NH2 substituents has attracted much less
attention.5,6 In a few cases, protected amines have been
employed.7-10 However, the direct use of heteroaromatics
bearing unprotected functions, such as NH2, would be more
useful in organic synthesis since it would allow us to avoid
the protection/deprotection sequence and would provide a
more environmentally and economically attractive access to
such arylated heteroaromatics.8,9 Therefore, the discovery
of effective conditions, for the direct coupling of such
aminothiophenes with aryl halides, would be a considerable
advantage for industrial applications and for sustainable
development. Here, we wish to report on the reaction of
† Laboratoire d’Hydrome´tallurgie et Chimie Inorganique Mole´culaire.
‡ Institut Sciences Chimiques de Rennes.
(1) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (c) Doucet, H.;
Hierso, J. C. Curr. Opin. Drug DiscoVery DeV. 2007, 10, 672. (d) Campeau,
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (e) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f) Li, B.-J.; Yang,
S.-D.; Shi, Z.-J. Synlett 2008, 949. (g) Bellina, F.; Rossi, R. Tetrahedron
2009, 65, 10269. (h) Ackermann, L.; Vincente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792. (i) Roger, J.; Gottumukkala, A. L.; Doucet,
(3) For selected recent examples of direct arylations of thiophenes: (a)
Fournier Dit Chabert, J.; Chatelain, G.; Pellet-Rostaing, S.; Bouchu, D.;
Lemaire, M. Tetrahedron Lett. 2006, 47, 1015. (b) Nakano, M.; Satoh, T.;
Miura, M. J. Org. Chem. 2006, 71, 8309. (c) David, E.; Pellet-Rostaing,
S.; Lemaire, M. Tetrahedron 2007, 63, 8999. (d) Turner, G. L.; Morris,
J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996. (e) Amaladass,
P.; Clement, J. A.; Mohanakrishnan, A. K. Tetrahedron 2007, 63, 10363.
(f) Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10,
1851.
H. ChemCatChem 2010, 2, 20
(2) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951
.
.
10.1021/ol101758w  2010 American Chemical Society
Published on Web 09/01/2010

Scheme 1
Figure 1. Articaine and its precursor.
thiophene derivatives bearing unprotected amino functions
with a set of electronically and sterically diverse aryl
bromides.
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 (Figure 1), which is actually the most
widely used local dental anesthetic in several European
countries.
First, we examined the influence of the base, solvent,
catalyst precursor, and reaction temperature for the coupling
of 4-(trifluoromethyl)bromobenzene with methyl 3-amino-
4-methylthiophene-2-carboxylate (Scheme 1, Table 1). We
observed that, in the course of this reaction, several
compounds can be obtained. However, the amination product
1f was not detected. On the other hand, the 2,5-diarylated
product 1b and the decarboxylated product 1c were obtained
in relatively 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 good solvent for direct arylations
of heteroaromatics.4j K2CO3, Na2CO3, or Cs2CO3 gave poor
conversions of 4-(trifluoromethyl)bromobenzene, and target
compound 1a was obtained only in traces (Table 1, entries
1-3). The use of acetates as the base gave better results,
and the desired compound 1a was obtained in 19-43%
selectivity together with moderate to large amounts of 1b
and 1c (Table 1, entries 4-6). It should be noted that the
inter- or intramolecular palladium-catalyzed amination of
some 3-aminothiophenes with aryl bromides has been
described using Cs2CO3 or K3PO4 as the bases in toluene.11
Interestingly, acetate appears to not be suitable to catalyze
the amination reaction, as no trace of 1f was detected. The
good performance of acetates as the bases is consistent with
a concerted metalation deprotonation (CMD) pathway.4k
Then, to reduce the amount of decarboxylated products, we
performed the reaction at 120 °C instead of 150 °C. At this
temperature, in the presence of KOAc as the base, DMAc
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)a
entry
solvent
base
catalyst
temp (°c)
convn (%)
ratio 1a:1b:1c:1e
1
2
3
4
5
6
7
8
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
NMP
K2CO3
Na2CO3
Cs2CO3
CsOAc
NaOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
150
150
150
150
150
150
120
120
120
120
120
120
120
120
120
5
13
11
98
43
100
100
100
93
63
100
92
-
2:0:1:8
2:1:4:0
43:37:12:2
28:5:5:4
19:66:11:3
93:3:1:1b
84:2:3:10
84:4:0:5
58:0:0:5
78:15:6:1
83:1:0:8
78:0:6:9
92:1:1:6
75:2:0:5
9
DMF
10
11
12
13
14
15
toluene
DMAc
DMAc
DMAc
DMAc
DMAc
c
Pd(OAc)2
Pd(OAc)2/dppb
1/2 [PdCl(C3H5)]2
1/2 [PdCl(C3H5)]2/dppe
100
100
83
1/2 [PdCl(C3H5)]2/2 PPh3
a Conditions: [Pd] (0.02 equiv), 4-(trifluoromethyl)bromobenzene (1 equiv), methyl 3-amino-4-methylthiophene-2-carboxylate (2 equiv), base (2 equiv),
20 h. Conversion of 4-(trifluoromethyl)bromobenzene. Traces of 4-(trifluoromethyl)benzene were also observed in some cases. b 1a was isolated in 82%
yield. c Pd(OAc)2, 0.01 equiv.
Org. Lett., Vol. 12, No. 19, 2010
4321

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 14 and 15).
Table 2. Direct Arylation of Methyl
3-Amino-4-methylthiophene-2-carboxylate (Scheme 2)b
Then, methyl 3-amino-4-methylthiophene-2-carboxylate
was coupled to a set of aryl bromides (Scheme 2, Table 2).
Scheme 2
The reactions performed with para-substituted electron-
deficient aryl bromides proceed conveniently. Selective
5-arylations were observed using 4-bromobenzaldehyde,
4-bromopropiophenone, 4-bromobenzonitrile, 4-bromoni-
trobenzene, or 4-bromofluorobenzene, resulting in 83-89%
yields of the products 2-6 (Table 2, entries 1-5). Electron-
rich aryl bromide, 4-bromoanisole, gave 8 in a lower yield
of 58% due to a partial conversion (Table 2, entry 7). As
expected, the meta-substituted aryl bromide, 3-(trifluorom-
ethyl)bromobenzene gave 9 in very high yield (Table 2, entry
9). Congested substrates, such as methyl 2-bromobenzoate
(4) For examples of palladium-catalyzed direct arylations using thiophenes
bearing formyl-, acetyl-, nitrile-, halo-, or methylalcohol substituents: (a)
Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1998, 71, 467. (b) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.;
Penalva, V.; Lemaire, M. J. Organomet. Chem. 1998, 567, 49. (c) Okazawa,
T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286.
(d) Hassan, J.; Gozzi, C.; Schulz, E.; Lemaire, M. J. Organomet. Chem.
2003, 687, 280. (e) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc.
2004, 126, 5074. (f) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.;
Mori, A. Org. Lett. 2005, 7, 5083. (g) Kobayashi, K.; Mohamed Ahmed,
M. S.; Mori, A. Tetrahedron 2006, 62, 9548. (h) Battace, A.; Lemhadri,
M.; Zair, T.; Doucet, H.; Santelli, M. AdV. Synth. Catal. 2007, 349, 2507.
(i) Derridj, F.; Gottumukkala, A. L.; Djebbar, S.; Doucet, H. Eur. J. Inorg.
Chem. 2008, 2550. (j) Roger, J.; Pozgˇan, F.; Doucet, H. Green Chem. 2009,
11, 425. (k) Lie´gaut, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826. (l) Dong, J. J.; Roger, J.; Doucet, H.
Tetrahedron Lett. 2009, 50, 2778. (m) Roger, J.; Pozˇgan, F.; Doucet, H.
AdV. Synth. Catal. 2010, 352, 696. (n) Lie´gault, B.; Petrov, I.; Gorlesky,
S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047.
a KOAc, 3 equiv. b 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.
(5) For examples of palladium-catalyzed direct arylations using free-
(NH2) adenines: Sahnoun, S.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.;
Alami, M. Tetrahedron Lett. 2008, 49, 7279.
or 2-bromobenzonitrile, were also found to be reactive under
these reaction conditions and gave 11 and 12 in 87 and 90%
yields, respectively (Table 2, entries 10 and 11).
(6) For intramolecular cyclizations of aniline derivatives: Ackermann,
L.; Althammer, A.; Mayer, P. Synthesis 2009, 3493.
(7) For examples of palladium-catalyzed direct arylations using protected
2-aminothiazoles: (a) Priego, J.; Gutierrez, S.; Ferritto, R.; Broughton, H. B.
Synlett 2007, 2957. (b) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9,
1449.
Pyridines are probably the most common heterocyclic
motif found in pharmaceutically active compounds. There-
fore, preparative methods of biheteroaryl derivatives contain-
ing pyridines remain an essential research topic in organic
synthesis. We observed that the coupling of 3- or 4-bro-
mopyridines or 3-bromoquinoline with methyl 3-amino-4-
methylthiophene-2-carboxylate also proceeds nicely to give
13-15 in good yields (Table 2, entries 12-14).
(8) For an example of palladium-catalyzed intramolecular direct aryla-
tions using a protected 2-aminofuran: Padwa, A.; Brodney, M. A.; Lynch,
S. M. J. Org. Chem. 2001, 66, 1716.
(9) For examples of palladium-catalyzed direct arylations using protected
2- or 3-aminothiophenes: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Synthesis 2008, 136. (b) Roger, J.; Doucet, H. Eur. J. Org.
Chem. 2010, 4412.
(10) For an example of palladium-catalyzed intramolecular direct
arylation using an aminothiophene derivative: Ferreira, I. C. F. R.; Queiroz,
M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 3737.
As the decarboxylation of methyl 3-amino-4-methylth-
iophene-2-carboxylate in the presence of a relatively strong base
is quite easy, we examined the reactivity of this substrate using
(11) (a) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. Tetrahe-
dron 2006, 62, 11100. (b) Carril, M.; SanMartin, R.; Dominguez, E.; Tellitu,
I. Tetrahedron 2007, 63, 690.
4322
Org. Lett., Vol. 12, No. 19, 2010

to block this reactive carbon and to provide alternative
regioisomeric arylthiophenes.
Table 3. Direct Arylations of Aminothiophene Derivativese
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 3, entry 6).
The target product 1b was obtained in 70% yield. The
synthesis of nonsymmetrically 2,5-diarylated thiophenes is
also possible. Compound 17b reacted with 4-bromotoluene
gave 18 in 75% yield (Table 3, entry 7).
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
presence of 1-bromonaphthalene, we observed the formation
of a mixture of the 4- and 5-arylated products 19a and 19b
in 52% and 12% yields, respectively (GC ratio 19a:19b )
77:23) (Table 3, entry 8).
Finally, we examined the influence of the substituent
distribution on the thiophene ring. A permutation of the
amino and ester substituents was found to drastically modify
the thiophene reactivity. No formation of product 20 was
detected in the presence of 4-bromobenzonitrile using similar
reaction conditions (Scheme 4). This result reveals that the
a KOH, 1.5 equiv was added. b KOAc (2 equiv). c Aryl bromide (2
equiv), thiophene derivative (1 equiv), KOAc (1.5 equiv), KOH (1.5 equiv).
d 120 °C. e Conditions: PdCl(C3H5)(dppb) (0.02 equiv), aryl bromide (1
equiv), thiophene derivative (2 equiv), KOAc (1.5 equiv), DMAc, 20 h,
150 °C.
Scheme 4
a mixture of KOH and KOAc as the bases (Table 3, entries 1
and 2). Using these conditions, only the 2-arylated products
16a and 17a were isolated. No formation of the other regioi-
somers or diarylated thiophenes was detected. As expected, the
direct arylation of 3-amino-4-methylthiophene also gave regi-
oselectively 16a, 17a, or 1d in good yields (Table 3, entries
3-5). This high regioselectivity in favor of the arylation on
carbon C2 might be due either to the coordination of the amino
substituent to palladium or the electronic factors.
electronic effect of the amino group on thiophene is
important.
In summary, we have demonstrated that when appropriate
reaction conditions are employed the palladium-catalyzed
direct arylation of some free NH2-substituted thiophene
derivatives proceeds nicely with a wide variety of aryl
bromides.
It should be noted that products 1c or 17b can be obtained
in good yields by decarboxylation of 1a or 13 using basic
To our knowledge, this is the first method for direct
arylation of free NH2-substituted thiophenes. The most
reactive carbon for the direct arylations of 3-aminothiophenes
appears to be the carbon C2. However, the presence of an
ester substituent on C2 was found to be useful to block this
highly reactive position to provide the 5-arylated thiophenes.
Scheme 3
Acknowledgment. J. R. is grateful to “Ministe`re de la
Recherche” for a grant. We thank the CNRS and “Rennes
Metropole” for providing financial support and PCAS SA
for providing some aminothiophenes.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
conditions (Scheme 3). Therefore, the presence of the ester
substituents on carbon C2 of thiophene appears to be useful
OL101758W
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