Palladium-catalyzed direct arylations of five-membered heteroarenes bearing N-monoalkylcarboxamide substituents

Article abstract of DOI:10.1002/ejoc.201100312

The palladium-catalyzed direct arylation of furan, thiophene, pyrrole, or pyrazole derivatives bearing CONHR substituents on C2, C3, or C5 with aryl bromides was studied. The use of KOAc as the base, DMAc as the solvent, and PdCl(C₃H₅)(dppb) as the catalyst was found to give regioselectively and without decarbamoylation the arylated heteroaromatics. Under these conditions, the amide substituent on the heteroaromatic does not act as a directing group. A wide range of functional groups such as acetyl, formyl, ester, nitrile, trifluoromethyl, and fluoro on the aryl bromide is tolerated. The palladium-catalyzed direct arylation of furan, thiophene, pyrrole, or pyrazole derivatives bearing CONHR substituents on C2, C3, or C5 with aryl bromides was studied. The use of KOAc as the base, DMAc as the solvent, and PdCl(C₃H₅)(dppb) as the catalyst was found to give regioselectively the arylated heteroaromatics.

Full text of DOI:10.1002/ejoc.201100312

FULL PAPER
DOI: 10.1002/ejoc.201100312
Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
Bearing N-Monoalkylcarboxamide Substituents
Nouria Laidaoui,[a,b] Julien Roger,[a] Abdellah Miloudi,[b] Douniazad El Abed,*[b] and
Henri Doucet*[a]
Keywords: Arylation / Heterocycles / Homogeneous catalysis / C–H activation / Palladium
The palladium-catalyzed direct arylation of furan, thiophene,
pyrrole, or pyrazole derivatives bearing CONHR substituents
on C2, C3, or C5 with aryl bromides was studied. The use of
KOAc as the base, DMAc as the solvent, and PdCl(C3H5)-
(dppb) as the catalyst was found to give regioselectively and
without decarbamoylation the arylated heteroaromatics. Un-
der these conditions, the amide substituent on the hetero-
aromatic does not act as a directing group. A wide range of
functional groups such as acetyl, formyl, ester, nitrile, tri-
fluoromethyl, and fluoro on the aryl bromide is tolerated.
The classical palladium-catalyzed reactions such as Stille,
Suzuki, or Negishi couplings allow the formation of a wide
variety of biaryls.[2] However, for these couplings, the pre-
liminary synthesis of organometallic derivatives is required.
Moreover, these reactions provide a stoichiometric amount
of metallic side products, from which undesired contami-
nation could be potentially appalling for pharmaceutical,
agrochemical, and related biological applications.
In 1990, Ohta and co-workers reported that the 2- or 5-
arylation of several heteroaromatics, including furans and
thiophenes, with aryl halides proceed in moderate to good
yields through C–H bond activation by using Pd(PPh3)4 as
the catalyst.[3] Since these results, the palladium-catalyzed
direct arylation of heteroaromatics with aryl halides has
proved to be a very powerful method for the synthesis of a
wide variety of arylated heterocycles.[4–8]
Introduction
The easy access to a variety of heteroaromatics bearing
functional groups such as amides is an important field for
research in organic chemistry due to the biological proper-
ties of some of these derivatives. For example, Oxacillin and
its derivatives are used as antibiotics, Atorvastatin is em-
ployed against cholesterol, and Rimonabant is an anorectic
antiobesity drug (Figure 1).[1]
The direct arylation of quite simple furan, thiophene, or
pyrrole derivatives has been largely described. On the other
hand, heteroaromatics bearing amide substituents have
been rarely employed.[9–11] A few thiophene derivatives sub-
stituted on C2 or C3 by an amide have been used in palla-
dium-catalyzed direct intramolecular arylations.[10,11] The
intermolecular direct arylation using a thiophene with a
carboxanilide function on C2 has been reported by Miura
and co-workers.[9] It is worth noting that the regioselectivity
of the phenylation depends on the nature of the carboxanil-
ide function. The initial phenylation of a thiophene substi-
tuted on C2 by CONHPh takes place preferably at the 3-
position, followed by the second phenylation at the 5-posi-
tion (Scheme 1, top), whereas the reaction of a thiophene
substituted on C2 by CON(C5H10) (tertiary amide) occurs
in the reverse order (Scheme 1, bottom). Moreover, in some
cases, the carbamoyl group was cleaved to give 2,3,5-triaryl-
thiophenes when an excess amount of phenyl triflate was
employed.[9a] With such substrates, the formation of mix-
Figure 1. Examples of bioactive derivatives.
[a] Institut Sciences Chimiques de Rennes, UMR 6226 CNRS –
Université de Rennes 1, “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
Fax: +33-2-23236939
E-mail: henri.doucet@univ-rennes1.fr
[b] Laboratoire de Chimie Fine, Département de Chimie, Faculté
des Sciences, Université d’Oran Es-Sénia,
B. P. 1524, EL M’naouer, Oran 31100, Algérie
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4373

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
tures of 5-arylated and 3,5-diarylated thiophenes had also Table 1. Palladium-catalyzed coupling of N-benzyl-2-furamide with
aryl bromides (Scheme 3).[a]
been observed.[9b] Miura’s group also studied the reactivity
of N-phenyl-3-thiophenecarboxamide.[9c] This reactant was
successfully triarylated on C2, C4, and C5.
Scheme 1. Reported regioselectivity for the arylation of thiophene-
carboxamides.
The palladium-catalyzed direct regioselective arylation of
amide-substituted heteroaromatics should provide cost-ef-
fective and environmentally attractive access for the prepa-
ration of useful heteroaromatic derivatives. The major by-
products of the reaction would be a base associated to HX,
instead of metallic salts produced under more classical
cross-coupling procedures[1,2] such as Suzuki, Negishi, or
Stille reactions. Moreover, the method avoids the prelimi-
nary preparation of a requisite organometallic, reducing the
number of steps to prepare these compounds. Herein, we
wish to report on the use of amide-substituted heteroarom-
atics for palladium-catalyzed direct arylations, using a wide
variety of electronically and sterically diverse aryl and het-
eroaryl bromides.
Results and Discussion
We initially studied the reactivity of N-benzyl-2-furamide
(3) with aryl bromides. We had previously observed that the
coupling reaction using methyl furan-2-carboxylate (1) and
4-bromobenzonitrile gave the desired 5-arylated methyl
furan-2-carboxylate 2 (Scheme 2).[12a] However, this com-
pound was obtained in a low yield of 26% due to partial
decarboxylation of this furan derivative. In the course of
this reaction, a mixture of 2, 2-arylfuran, and 2,5-diaryl-
furan was formed. Similar mixtures of products were ob-
tained in the presence of several other aryl bromides, and
shorter reaction times did not improve the yields.
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), N-benzyl-2-fur-
amide (1.5 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.),
DMAc, 150 °C, 16 h, isolated yields.
Scheme 2. Coupling of methyl furan-2-carboxylate with 4-bromo-
benzonitrile.
4374
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
As the amide function was found to be more stable than
the ester function, the yields of coupling products in the
presence of 3 were higher. We observed that with KOAc as
the base, and DMAc as the solvent, using only 0.5 mol-%
PdCl(C3H5)(dppb) as the catalyst, 5-arylated furans 4–16
were regioselectively obtained in good yields (Scheme 3,
Table 1). It should be noted that under these reaction condi-
tions, the amide substituent does not act as a directing
group for the arylation, and no formation of 3-arylated
furan derivatives was detected. Moreover, in the course of
this reaction, no decarbamoylation by C–N fission was ob-
served. Similar regioselectivities (arylation on C5) had been
Scheme 3. Coupling of 2-furamides with aryl bromides.
A wide range of aryl bromides was employed. In the
observed for the direct arylations of various heteroaromat- presence of electron-deficient aryl bromides such as 4-bro-
ics bearing –CH2NHCOR substituents on C2.[13]
moacetophenone, 4-bromobenzaldehyde, methyl 4-bromo-
Table 2. Palladium-catalyzed coupling of 2-furamide derivatives with aryl bromides (Scheme 3).
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), 2-furamide derivative (1.5 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.), DMAc,
150 °C, 16 h, isolated yields.
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4375

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
benzoate, 4-bromobenzonitrile, or 4-(trifluoromethyl)bro- arylated thiophene when the reaction was conducted in the
mobenzene and 0.5 mol-% catalyst, products 4–7 were ob- presence of phenyl triflate in toluene with Cs2CO3 as the
tained in good yields (Table 1, Entries 1–5). The use of the base (Scheme 1, top).[9a] Using our reaction conditions,
meta-substituted aryl bromides 3-bromoacetophenone, 3- KOAc as the base, DMAc as the solvent, and 0.5 mol-%
(trifluoromethyl)bromobenzene, and 3-bromonitrobenzene PdCl(C3H5)(dppb) as the catalyst, only the arylation at C5
also gave 5-arylated furans 10–12 in good yields (Table 1, of thiophene to give products 33a and 34–40 was observed.
Entries 7–9). Coupling with the more-hindered substrates 2- On the other hand, the use of Miura’s conditions (Cs2CO3
bromobenzonitrile and 1-bromonaphthalene gave 13 and 15 and toluene) gave regioselectively 33b in 66% yield (Table 3,
in 88 and 81% yield, respectively (Table 1, Entries 10 and Entry 2). The formation of C3-arylated products observed
12). On the other hand, in the presence of 3-bromopyridine
a lower yield of 57% in 16 was obtained due to partial
Table 3. Palladium catalyzed coupling of thiophene-2-carboxylic
conversion of this aryl bromide (Table 1, Entry 13).
Then, the scope of this reaction for the coupling of other
2-furamides was investigated (Scheme 3, Table 2). In the
presence of N-n-propyl-2-furamide (17) and electron-de-
ficient aryl bromides such as 2- or 3-bromobenzonitriles or
2-, 3-, or 4-(trifluoromethyl)bromobenzenes and 0.5 mol-%
catalyst, products 18–22 were obtained in 60–83% yield
(Table 2, Entries 1–5). The use of 4-bromopyridine also
gave desired product 23 in good yield (Table 2, Entry 6).
The reaction of furan-2-carbonyl chloride with 2-methoxye-
thylamine gave substrate 25. Arylation of 25 with methyl 4-
bromobenzoate produced 26 in 90% yield (Table 2, En-
try 8). Finally, the arylation of N-benzyl-2-furamide (27)
with 2-(trifluoromethyl)bromobenzene also gave regioselec-
tively the arylation at C5 to produce 28 in 72% yield
(Table 2, Entry 9).
acid benzylamide with aryl bromides (Scheme 5).
Then, we studied the reactivity of thiophene-2-carboxylic
acid benzylamide (32). We had previously reported that, in
the presence of methyl thiophene-2-carboxylate (29), the di-
rect arylation proceeds nicely, and 5-arylated thiophenes 30
and 31 could be obtained in good yields without the forma-
tion of important amounts of decarboxylated products
(Scheme 4).[14]
Scheme 4. Coupling of methyl thiophene-2-carboxylate with aryl
bromides.
However, to determine the regioselectivity of the direct
arylation of 32 under our reaction conditions, its coupling
with a few aryl bromides was studied (Scheme 5, Table 3).
Miura and co-workers had observed the formation of a 3-
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), thiophene-2-
carboxylic acid benzylamide (1.5 equiv.), aryl bromide (1 equiv.),
KOAc (2 equiv.), DMAc, 150 °C, 16 h, isolated yields. [b] Cs2CO3
(2 equiv.), toluene, 110 °C.
Scheme 5. Coupling of thiophene-2-carboxylic acid benzylamide
with aryl bromides.
4376
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
with secondary amides in the presence of Cs2CO3 as the Table 4. Palladium-catalyzed coupling of 1-methylpyrrole-2-carb-
oxylic acid benzylamide with aryl bromides (Scheme 7).
base (Scheme 1) probably comes from a coordination-as-
sisted mechanism.[9] On the other hand, when KOAc is em-
ployed as the base, the reaction probably proceeds through
a concerted-metalation–deprotonation mechanism (CMD)
to give arylation at C5.[15]
Next, we examined the reactivity of an amide-substituted
pyrrole. We previously observed that for coupling reactions
of aryl bromides with methyl 1-methyl-2-pyrrolecarboxyl-
ate, mixtures of the 5-arylated pyrroles and 2-arylpyrroles
arising from decarboxylation were obtained when the reac-
tions were stopped after 17 h. Up to 50% of these decarb-
oxylated pyrroles could be formed. As this decarboxylation
process was found to be relatively slow, as compared to the
palladium-catalyzed 5-arylation rate, when the reactions
were stopped after 2–5 h, the target products could be ob-
tained in moderate to high yields (Scheme 6).[16b]
Scheme 6. Coupling of methyl N-methylpyrrole-2-carboxylate with
4-bromobenzonitrile.
Therefore, to have more reliable access to arylpyrroles
substituted by amides, we examined the direct arylation of
1-methylpyrrole-2-carboxylic acid benzylamide (43) with
various aryl bromides (Scheme 7, Table 4). Again, the reac-
tion was found to be very regioselective, as only the C5
arylation products were isolated. The amide function was
found to be much more stable than the ester, as no decar-
bamoylation was detected. The reaction of 2-, 3-, or 4-bro-
mobenzonitriles, 3-(trifluoromethyl)bromobenzene, methyl
4-bromobenzoate, or 3- or 4-bromopyridine gave the de-
sired coupling products 44, 45, 47–51 in 70–78% yield
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), 1-methylpyrrole-
(Table 4, Entries 1, 2, and 4–8). In the presence of 3-bro-
2-carboxylic acid benzylamide (1.5 equiv.), aryl bromide (1 equiv.),
KOAc (2 equiv.), DMAc, 150 °C, 16 h, isolated yields.
mobenzaldehyde the formation of unidentified side prod-
ucts was observed and 46 was obtained in only 48% yield
(Table 4, Entry 3).
Scheme 7. Coupling of 1-methylpyrrole-2-carboxylic acid benzyl-
amide with aryl bromides.
Scheme 8. Coupling of 2-methylfuran-3-carboxylic acid benzyl-
amide with aryl bromides.
We also employed a furan substituted by an amide on
C3 (Scheme 8, Table 5). The arylations proceed nicely with
a variety of aryl bromides, and expected products 53–59
Finally, we examined the reactivity of a pyrazole substi-
were obtained in good yields in all cases. Again, no forma- tuted on the 5-position by an amide (Scheme 10). We had
tion of other isomers or decarbamoylated products was de- previously observed that when using ester-substituted pyr-
tected.
azole 60 in the presence of Pd(OAc)2/P(Ad)2nBu as the cat-
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4377

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
Table 5. Palladium-catalyzed coupling of 2-methylfuran-3-carbox-
ylic acid benzylamide with aryl bromides (Scheme 8).
Scheme 9. Coupling of ethyl 1,3-dimethylpyrazole-5-carboxylate
with aryl bromides.
69 were obtained in good yields using para-, meta-, or or-
tho-substituted aryl bromides and an heteroaryl bromide in
the presence of only 0.5 mol-% of PdCl(C3H5)(dppb) as the
catalyst.
Scheme 10. Coupling of 1-ethyl-3-methylpyrazole-5-carboxylic acid
benzylamide with aryl bromides.
Conclusions
In conclusion, these results demonstrate that several het-
eroaromatics substituted by CONHR groups on C2, C3, or
C5 can be employed for palladium-catalyzed direct aryla-
tions. Amide functions appear to be more stable than ester
functions, as no decarbamoylation was observed in the
course of these reactions. Therefore, for the synthesis of aryl-
ated amide-substituted heteroaromatics by palladium-cata-
lyzed direct arylations, the preliminary transformation of
esters into amides should be preferred. A low catalyst load-
ing (0.5 mol-%) gave regioselectively the arylated com-
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), 2-methylfuran-3-
carboxylic acid benzylamide (1.5 equiv.), aryl bromide (1 equiv.),
KOAc (2 equiv.), DMAc, 150 °C, 20 h, isolated yields.
alyst, 4-arylated products 61 and 62 were obtained in very pounds. It should be noted that in the presence of thio-
low yields (Scheme 9).[17b]
phene-2-carboxylic acid benzylamide, the 3-arylation prod-
To the best of our knowledge, no example of palladium- ucts were not detected. When DMAc was employed as the
catalyzed direct arylation of amide-substituted pyrazoles solvent and KOAc as the base, the amide substituent on the
has been reported so far. Again, we observed that the use heteroaromatics did not act as a directing group for the
of amide-substituted compound 63 gave better yields than direct arylation. A wide range of functions such as acetyl,
the use of corresponding ester-substituted pyrazole 60 formyl, ester, nitrile, trifluoromethyl, and fluoro on the aryl
(Schemes 9 and 10, Table 6). Desired coupling products 64– bromide is tolerated. The major byproducts of these cou-
4378
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
Table 6. Palladium-catalyzed coupling of 1-ethyl-3-methylpyrazole-
Experimental Section
5-carboxylic acid benzylamide with aryl bromides (Scheme 10).
General Methods: DMAc (99%) was purchased from Acros.
[Pd(C3H5)Cl]2, 1,4-bis(diphenylphosphanyl)butane (98%), and
KOAc (99%) were purchased from Alfa Aesar. These compounds
were not purified before use. 1H and 13C NMR spectra were re-
corded with a Bruker 300 MHz spectrometer.
Preparation of the PdCl(C3H5)(dppb) Catalyst: An oven-dried, 40-
mL Schlenk tube equipped with a magnetic stirring bar under an
argon atmosphere was charged with [Pd(C3H5)Cl]2 (182 mg,
0.5 mmol) and dppb (426 mg, 1 mmol). Anhydrous dichlorometh-
ane (10 mL) was added, and then the solution was stirred at room
temperature for 20 min. The solvent was removed in vacuo. The
yellow powder was used without purification. 31P NMR (81 MHz,
CDCl3) δ = 19.3 (s) ppm.
General Procedure for Direct Arylation Reactions: In a typical ex-
periment, the aryl bromide (1 mmol), heteroaryl derivative
(1.5 mmol), KOAc (0.196 g, 2 mmol), and PdCl(C3H5)(dppb)
(3.4 mg, 0.005 mmol) were dissolved in DMAc (4 mL) under an
argon atmosphere. The reaction mixture was stirred at 150 °C for
16 h. Then, the solvent was evaporated, and the product was puri-
fied by silica gel column chromatography.
N-Benzyl-2-furamide (3):[18] The reaction of furan-2-carbonyl chlo-
ride (0.312 g, 2.4 mmol), benzylamine (0.214 g, 2 mmol) in triethyl-
amine (4 mL) and dichloromethane (30 mL) at room temperature
over 3 h gave 3 in 75% (0.302 g) yield after addition of an H2O/
HCl solution, extraction with dichloromethane, drying (MgSO4),
and purification by silica gel column chromatography. 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.20 (m, 6 H), 7.18 (d, J = 3.0 Hz, 1
H), 6.85–6.70 (m, 1 H), 6.55–6.45 (m, 1 H), 4.67 (d, J = 5.7 Hz, 2
H) ppm.
5-(4-Acetylphenyl)furan-2-carboxylic Acid Benzylamide (4): 4-Bro-
moacetophenone (0.199 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
1
forded 4 in 74% (0.236 g) yield. H NMR (300 MHz, CDCl3): δ =
7.96 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.40–7.20 (m,
6 H), 6.88 (d, J = 3.0 Hz, 1 H), 6.85–6.75 (m, 1 H), 4.67 (d, J =
5.7 Hz, 2 H), 2.62 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
196.2, 157.1, 153.1, 146.8, 136.9, 135.5, 132.5, 127.9, 127.8, 126.9,
126.7, 123.3, 115.7, 108.5, 42.2, 25.6 ppm. C20H17NO3 (319.35):
calcd. C 75.22, H 5.37; found C 75.01, H 5.20.
5-(4-Formylphenyl)furan-2-carboxylic Acid Benzylamide (5): 4-Bro-
mobenzaldehyde (0.185 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
1
forded 5 in 67% (0.204 g) yield. H NMR (300 MHz, CDCl3): δ =
9.97 (s, 1 H), 7.90 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H),
7.47 (d, J = 3.8 Hz, 1 H), 7.40–7.20 (m, 6 H), 6.40–6.25 (m, 1 H),
4.60 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
191.9, 158.5, 154.3, 148.5, 138.4, 136.1, 135.2, 130.7, 129.2, 128.4,
128.1, 125.1, 117.2, 110.5, 43.7 ppm. C19H15NO3 (305.33): calcd. C
74.74, H 4.95; found C 74.71, H 4.80.
Methyl 4-(5-Benzylcarbamoylfuran-2-yl)benzoate (6): Methyl 4-bro-
mobenzoate (0.215 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) afforded
6 in 87% (0.291 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.98
(d, J = 8.3 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 7.40–7.20 (m, 5 H),
7.22 (d, J = 3.6 Hz, 1 H), 6.80 (d, J = 3.6 Hz, 1 H), 6.80–6.75 (m,
1 H), 4.67 (d, J = 5.7 Hz, 2 H), 3.88 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.9, 158.5, 154.6, 148.1, 138.4, 133.9,
130.6, 130.2, 129.2, 128.4, 128.1, 124.6, 117.1, 109.7, 52.7,
43.7 ppm. C20H17NO4 (335.35): calcd. C 71.63, H 5.11; found C
71.50, H 5.04.
[a] Conditions: PdCl(C3H5)(dppb) (0.005 equiv.), 1-ethyl-3-methyl-
pyrazole-5-carboxylic acid benzylamide (1.5 equiv.), aryl bromide
(1 equiv.), KOAc (2 equiv.), DMAc, 150 °C, 16 h, isolated yields.
plings are AcOH/KBr instead of metallic salts with more
classical coupling procedures. For these reasons, this reac-
tion should give economically viable and environmentally
attractive access to arylated amide-substituted heteroarom-
atics.
5-(4-Cyanophenyl)furan-2-carboxylic Acid Benzylamide (7): 4-Bro-
mobenzonitrile (0.182 g, 1 mmol), 3 (0.302 g, 1.5 mmol), and
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4379

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
KOAc (0.196 g, 2 mmol) afforded 7 in 84% (0.254 g) yield. 1H (m, 9 H), 7.10 (d, J = 3.6 Hz, 1 H), 4.71 (d, J = 5.9 Hz, 2 H) ppm.
NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2 H), 7.58 (d,
J = 8.3 Hz, 2 H), 7.40–7.20 (m, 6 H), 6.90–6.80 (m, 2 H), 4.67 (d,
J = 5.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.4,
153.6, 148.6, 138.3, 133.8, 133.1, 129.2, 128.2, 128.1, 125.1, 118.9,
117.1, 112.0, 110.5, 43.6 ppm. C19H14N2O2 (302.33): calcd. C
75.48, H 4.67; found C 75.31, H 4.60.
13C NMR (75 MHz, CDCl3): δ = 158.0, 151.0, 147.8, 138.0, 134.4,
133.0, 131.8, 128.7, 128.4, 127.9, 127.6, 126.4, 119.1, 116.1, 111.4,
107.5, 43.3 ppm. C19H14N2O2 (302.33): calcd. C 75.48, H 4.67;
found C 75.67, H 4.69.
5-(2-Trifluoromethylphenyl)furan-2-carboxylic Acid Benzylamide
(14):[20] 2-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 3
1
5-(4-Trifluoromethylphenyl)furan-2-carboxylic Acid Benzylamide (0.302 g, 1.5 mmol) afforded 14 in 80% (0.276 g) yield. H NMR
(8): 4-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol),
3
(300 MHz, CDCl3): δ = 7.78 (d, J = 8.0 Hz, 1 H), 7.68 (d, J =
8.0 Hz, 1 H), 7.49 (t, J = 7.7 Hz, 1 H), 7.46–7.20 (m, 7 H), 6.79 (d,
(0.302 g, 1.5 mmol), and KOAc (0.196 g, 2 mmol) afforded 8 in
62% (0.214 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J J = 3.6 Hz, 1 H), 6.80–6.75 (m, 1 H), 4.68 (d, J = 5.9 Hz, 2 H) ppm.
= 8.3 Hz, 2 H), 7.60 (d, J = 8.3 Hz, 2 H), 7.40–7.20 (m, 5 H), 7.18
5-Naphthalen-1-ylfuran-2-carboxylic Acid Benzylamide (15): 1-Bro-
(d, J = 3.6 Hz, 1 H), 6.80 (d, J = 3.6 Hz, 1 H), 6.80–6.75 (m, 1 H),
monaphthalene (0.207 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
4.68 (d, J = 5.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
1
forded 15 in 81% (0.265 g) yield. H NMR (300 MHz, CDCl3): δ
157.1, 152.7, 146.7, 136.9, 131.7, 129.2 (q, J = 32.8 Hz), 127.8,
= 8.35–8.25 (m, 1 H), 7.95–7.20 (m, 12 H), 6.98–6.80 (m, 1 H),
126.9, 126.7, 124.9 (q, J = 3.8 Hz), 123.5, 122.8 (q, J = 272.6 Hz),
6.82 (d, J = 3.6 Hz, 1 H), 4.69 (d, J = 5.9 Hz, 2 H) ppm. 13C NMR
115.7, 108.1, 42.2 ppm. C19H14F3NO2 (345.32): calcd. C 66.09, H
(75 MHz, CDCl3): δ = 158.8, 155.2, 149.7, 147.7, 138.5, 134.2,
4.09; found C 66.10, H 4.04.
130.1, 129.2, 129.1, 128.3, 128.0, 127.8, 127.5, 127.4, 126.7, 125.6,
5-(4-Fluorophenyl)furan-2-carboxylic Acid Benzylamide (9): 4-Bro-
mofluorobenzene (0.175 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
forded 9 in 66% (0.195 g) yield. H NMR (300 MHz, CDCl3): δ =
7.77 (dd, J = 8.5, 5.5 Hz, 2 H), 7.40–7.20 (m, 5 H), 7.18 (d, J =
3.6 Hz, 1 H), 7.02 (t, J = 8.5 Hz, 2 H), 6.80–6.70 (m, 1 H), 6.67 (d, J
= 3.6 Hz, 1 H), 4.68 (d, J = 5.9 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 161.8 (d, J = 249.1 Hz), 157.3, 153.5, 145.8, 137.1,
127.7, 126.9, 126.6, 125.3 (d, J = 8.3 Hz), 124.9, 115.6, 114.9 (d, J
= 21.9 Hz), 106.0, 42.1 ppm. C18H14FNO2 (295.31): calcd. C 73.21,
H 4.78; found C 73.08, H 4.77.
125.4, 116.7, 112.1, 43.6 ppm. C22H17NO2 (327.38): calcd. C 80.71,
H 5.23; found C 80.60, H 4.99.
1
5-Pyridin-3-ylfuran-2-carboxylic Acid Benzylamide (16): 3-Bromo-
pyridine (0.158 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) afforded 16
1
in 57% (0.158 g) yield. H NMR (300 MHz, CDCl3): δ = 8.85 (s,
1 H), 8.48 (d, J = 3.9 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.40–
7.20 (m, 7 H), 6.98–6.85 (m, 1 H), 6.73 (d, J = 3.6 Hz, 1 H), 4.63
(d, J = 5.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.5,
152.8, 149.6, 148.2, 146.2, 138.5, 131.9, 129.1, 128.3, 128.0, 126.2,
124.0, 116.8, 109.0, 43.6 ppm. C17H14N2O2 (278.31): calcd. C
73.37, H 5.07; found C 73.54, H 4.98.
5-(3-Acetylphenyl)furan-2-carboxylic Acid Benzylamide (10): 3-Bro-
moacetophenone (0.199 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
N-n-Propyl-2-furamide (17):[21] The reaction of furan-2-carbonyl
chloride (0.312 g, 2.4 mmol) and n-propylamine (0.118 g, 2 mmol)
in triethylamine (4 mL) and dichloromethane (30 mL) at room tem-
perature over 3 h gave 17 in 72% (0.220 g) yield after addition of
an H2O/HCl solution, extraction with dichloromethane, drying
(MgSO4), and purification by silica gel column chromatography.
1H NMR (300 MHz, CDCl3): δ = 7.32 (m, 1 H), 6.91 (m, 1 H),
6.90–6.70 (m, 1 H), 6.32 (m, 1 H), 3.30 (q, J = 7.5 Hz, 2 H), 1.47
(sext., J = 7.5 Hz, 2 H), 0.81 (t, J = 7.5 Hz, 3 H) ppm.
1
forded 10 in 81% (0.258 g) yield. H NMR (300 MHz, CDCl3): δ
= 8.21 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.54 (t, J = 8.4 Hz, 1 H),
7.50–7.30 (m, 5 H), 7.21 (d, J = 3.6 Hz, 1 H), 6.85–6.80 (m, 1 H),
6.80 (d, J = 3.6 Hz, 1 H), 4.68 (d, J = 5.9 Hz, 2 H), 2.61 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.7, 157.2, 153.3,
146.4, 137.1, 136.6, 129.1, 128.1, 127.8, 127.7, 127.4, 126.9, 126.6,
122.8, 115.7, 107.3, 42.2, 25.7 ppm. C20H17NO3 (319.35): calcd. C
75.22, H 5.37; found C 75.04, H 5.27.
5-(3-Trifluoromethylphenyl)furan-2-carboxylic Acid Benzylamide
5-(4-Trifluoromethylphenyl)furan-2-carboxylic Acid Propylamide
(11): 3-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 3
(18): 4-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 17
1
(0.302 g, 1.5 mmol) afforded 11 in 62% (0.214 g) yield. H NMR
1
(0.230 g, 1.5 mmol) afforded 18 in 63% (0.187 g) yield. H NMR
(300 MHz, CDCl3): δ = 7.90–7.70 (m, 2 H), 7.60–7.20 (m, 7 H),
7.18 (d, J = 3.6 Hz, 1 H), 6.80–6.75 (m, 2 H), 4.68 (d, J = 5.9 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.1, 152.7, 146.5,
130.7, 130.3 (q, J = 32.5 Hz), 129.3, 128.4, 127.8, 126.9, 126.7,
126.5, 124.1 (q, J = 3.6 Hz), 123.3 (q, J = 272.6 Hz), 120.1 (q, J =
3.9 Hz), 115.7, 107.6, 42.2 ppm. C19H14F3NO2 (345.32): calcd. C
66.09, H 4.09; found C 65.98, H 4.15.
(300 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2 H), 7.70 (d, J =
8.3 Hz, 2 H), 7.18 (d, J = 3.6 Hz, 1 H), 6.81 (d, J = 3.6 Hz, 1 H),
6.60–6.45 (m, 1 H), 3.39 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J =
7.5 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.2, 152.5, 147.0, 131.7, 126.1 (q, J = 32.0 Hz), 124.9
(q, J = 3.8 Hz), 123.8, 123.1 (q, J = 272.6 Hz), 115.2, 108.1, 40.0,
22.0, 10.4 ppm. C15H14F3NO2 (297.27): calcd. C 60.60, H 4.75;
found C 60.78, H 4.58.
5-(3-Nitrophenyl)furan-2-carboxylic Acid Benzylamide (12):[19] 3-
Bromonitrobenzene (0.202 g, 1 mmol) and 3 (0.302 g, 1.5 mmol)
5-(3-Trifluoromethylphenyl)furan-2-carboxylic Acid Propylamide
(19): 3-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 17
(0.230 g, 1.5 mmol) afforded 19 in 60% (0.178 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.88 (d, J = 8.2 Hz, 1 H),
7.70–7.50 (m, 2 H), 7.19 (d, J = 3.6 Hz, 1 H), 6.81 (d, J = 3.6 Hz,
1 H), 6.60–6.45 (m, 1 H), 3.39 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J
= 7.5 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.6, 153.9, 148.3, 130.8, 129.8, 129.7 (q, J =
1
afforded 12 in 77% (0.248 g) yield. H NMR (300 MHz, CDCl3):
δ = 8.52 (s, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1
H), 7.58 (t, J = 8.4 Hz, 1 H), 7.50–7.20 (m, 6 H), 6.90 (d, J =
3.6 Hz, 1 H), 6.80–6.70 (m, 1 H), 4.71 (d, J = 5.9 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.6, 151.4, 147.5, 146.8, 136.6,
129.9, 128.8, 128.7, 127.6, 126.8, 126.5, 121.7, 117.9, 115.5, 108.2,
42.0 ppm.
5-(2-Cyanophenyl)furan-2-carboxylic Acid Benzylamide (13): 2-Bro- 32.8 Hz), 127.9, 125.4 (q, J = 3.8 Hz), 122.8 (q, J = 272.6 Hz),
mobenzonitrile (0.182 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) af-
forded 13 in 88% (0.266 g) yield. H NMR (300 MHz, CDCl3): δ
= 7.78 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.50–7.20
121.5 (q, J = 3.8 Hz), 116.6, 109.0, 41.4, 23.5, 11.8 ppm.
C15H14F3NO2 (297.27): calcd. C 60.60, H 4.75; found C 60.51, H
4.68.
1
4380
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
5-(3-Cyanophenyl)furan-2-carboxylic Acid Propylamide (20): 3-Bro-
mobenzonitrile (0.182 g, 1 mmol) and 17 (0.230 g, 1.5 mmol) af-
forded 20 in 83% (0.211 g) yield. H NMR (300 MHz, CDCl3): δ
= 7.98 (s, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.60–7.40 (m, 2 H), 7.19
(d, J = 3.6 Hz, 1 H), 6.79 (d, J = 3.6 Hz, 1 H), 6.78–6.60 (m, 1 H),
3.39 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J = 7.5 Hz, 2 H), 0.98 (t, J
= 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.5, 152.9,
148.6, 131.9, 131.3, 130.1, 128.7, 128.1, 118.8, 116.5, 113.6, 109.4,
41.5, 23.4, 11.8 ppm. C15H14N2O2 (254.28): calcd. C 70.85, H 5.55;
found C 70.99, H 5.47.
= 158.8, 148.4, 144.3, 114.5, 112.4, 71.5, 59.2, 39.2 ppm. C8H11NO3
(169.18): calcd. C 56.80, H 6.55; found C 56.74, H 6.51.
1
Methyl 4-[5-(2-Methoxyethylcarbamoyl)furan-2-yl]benzoate (26):
Methyl 4-bromobenzoate (0.215 g, 1 mmol) and 25 (0.254 g,
1.5 mmol) afforded 26 in 90% (0.273 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.16 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.2 Hz, 2 H),
7.19 (d, J = 3.6 Hz, 1 H), 6.78 (d, J = 3.6 Hz, 1 H), 6.75–6.60 (m,
1 H), 3.94 (s, 3 H), 3.80–3.50 (m, 4 H), 3.51 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.9, 158.6, 154.6, 148.2, 133.9,
130.7, 130.6, 124.6, 116.8, 109.7, 71.6, 59.4, 52.7, 39.4 ppm.
C16H17NO5 (303.31): calcd. C 63.36, H 5.65; found C 63.47, H
5.70.
N-Phenyl-2-furamide (27):[22] The reaction of furan-2-carbonyl
chloride (0.312 g, 2.4 mmol) and aniline (0.186 g, 2 mmol) in trieth-
ylamine (4 mL) and dichloromethane (30 mL) at room temperature
over 3 h gave 27 in 83% (0.155 g) yield after addition of an H2O/
HCl solution, extraction with dichloromethane, drying (MgSO4),
and purification by silica gel column chromatography. 1H NMR
(300 MHz, CDCl3): δ = 8.25–8.15 (m, 1 H), 7.70 (d, J = 8.2 Hz, 2
H), 7.50–7.05 (m, 5 H), 7.56 (d, J = 3.3 Hz, 1 H) ppm.
5-(2-Cyanophenyl)furan-2-carboxylic Acid Propylamide (21): 2-Bro-
mobenzonitrile (0.182 g, 1 mmol), 17 (0.230 g, 1.5 mmol), and
KOAc (0.196 g, 2 mmol) afforded 21 in 67% (0.170 g) yield. 1H
NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 1 H), 7.67 (d,
J = 8.4 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1
H), 7.14 (d, J = 3.6 Hz, 1 H), 7.05 (d, J = 3.6 Hz, 1 H), 6.90–6.70
(m, 1 H), 3.41 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J = 7.5 Hz, 2 H),
0.98 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
158.5, 151.2, 148.5, 134.9, 133.4, 132.2, 128.7, 126.7, 119.7, 115.9,
111.5, 107.7, 41.5, 23.2, 11.8 ppm. C15H14N2O2 (254.28): calcd. C
70.85, H 5.55; found C 70.91, H 5.48.
5-(2-Trifluoromethylphenyl)furan-2-carboxylic Acid Phenylamide
(28):[20] 2-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and
27 (0.280 g, 1.5 mmol) afforded 28 in 72% (0.238 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 8.35–8.25 (m, 1 H), 8.00–7.00 (m, 10 H),
6.80 (d, J = 3.4 Hz, 1 H) ppm.
5-(2-Trifluoromethylphenyl)furan-2-carboxylic Acid Propylamide
(22): 2-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 17
1
(0.230 g, 1.5 mmol) afforded 22 in 74% (0.220 g) yield. H NMR
(300 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 1 H), 7.65 (d, J =
8.4 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H),
7.17 (d, J = 3.6 Hz, 1 H), 6.77 (d, J = 3.6 Hz, 1 H), 6.60–6.40 (m,
1 H), 3.38 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J = 7.5 Hz, 2 H), 0.98
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.2,
150.9, 147.2, 130.9, 129.3, 127.8, 127.2, 126.1 (q, J = 32.0 Hz),
126.0 (q, J = 5.8 Hz), 123.8 (q, J = 273.3 Hz), 114.3, 110.7 (q, J =
2.0 Hz), 39.8, 21.8, 10.2 ppm. C15H14F3NO2 (297.27): calcd. C
60.60, H 4.75; found C 60.71, H 4.74.
Thiophene-2-carboxylic Acid Benzylamide (32):[23] The reaction of
thiophene-2-carbonyl chloride (0.350 g, 2.4 mmol) and benzyl-
amine (0.214 g, 2 mmol) in triethylamine (4 mL) and dichlorometh-
ane (30 mL) at room temperature over 3 h gave 32 in 74% (0.321 g)
yield after addition of an H2O/HCl solution, extraction with
dichloromethane, drying (MgSO4), and purification by silica gel
1
column chromatography. H NMR (300 MHz, CDCl3): δ = 7.60–
7.20 (m, 7 H), 7.02 (dd, J = 5.0, 3.9 Hz, 1 H), 6.60–6.40 (m, 1 H),
4.70 (d, J = 5.7 Hz, 2 H) ppm.
5-Pyridin-4-ylfuran-2-carboxylic Acid Propylamide (23): 4-Bromo-
pyridine hydrochloride (0.194 g, 1 mmol) and 17 (0.230 g,
1.5 mmol) afforded 23 in 74% (0.170 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.57 (d, J = 5.3 Hz, 2 H), 7.49 (d, J = 5.3 Hz, 2 H),
7.16 (d, J = 3.6 Hz, 1 H), 6.84 (d, J = 3.6 Hz, 1 H), 6.78–6.60 (m,
1 H), 3.39 (q, J = 7.5 Hz, 2 H), 1.62 (sext., J = 7.5 Hz, 2 H), 0.98
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.4,
152.5, 150.6, 149.1, 136.9, 118.6, 116.3, 111.1, 41.4, 23.4, 11.8 ppm.
C13H14N2O2 (230.26): calcd. C 67.81, H 6.13; found C 67.60, H
6.04.
5-(4-Formylphenyl)thiophene-2-carboxylic Acid Benzylamide (33a):
4-Bromobenzaldehyde (0.185 g, 1 mmol) and 32 (0.325 g,
1.5 mmol) afforded 33a in 88% (0.283 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 9.97 (s, 1 H), 7.90 (d, J = 8.3 Hz, 2 H),
7.72 (d, J = 8.3 Hz, 2 H), 7.47 (d, J = 3.8 Hz, 1 H), 7.40–7.20 (m,
6 H), 6.40–6.25 (m, 1 H), 4.60 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 191.3, 161.3, 147.0, 139.3, 139.0, 137.8,
135.9, 130.5, 129.0, 128.9, 128.0, 127.8, 126.4, 125.2, 44.2 ppm.
C19H15NO2S (321.39): calcd. C 71.00, H 4.70; found C 70.81, H
4.51.
5-Pyridin-3-ylfuran-2-carboxylic Acid Propylamide (24): 3-Bromo-
pyridine (0.158 g, 1 mmol) and 17 (0.230 g, 1.5 mmol) afforded 24
1
3-(4-Formylphenyl)thiophene-2-carboxylic Acid Benzylamide (33b):
4-Bromobenzaldehyde (0.185 g, 1 mmol), 32 (0.325 g, 1.5 mmol),
PdCl(C3H5)(dppb) (3.4 mg, 0.005 mmol), and Cs2CO3 (0.652 g,
2 mmol) in toluene (4 mL) at 110 °C under an argon atmosphere
in 58% (0.133 g) yield. H NMR (300 MHz, CDCl3): δ = 8.80 (s,
1 H), 8.48 (d, J = 3.9 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.23 (dd,
J = 8.0, 3.9 Hz, 1 H), 7.12 (d, J = 3.6 Hz, 1 H), 6.80–6.70 (m, 1
H), 6.70 (d, J = 3.6 Hz, 1 H), 3.39 (q, J = 7.5 Hz, 2 H), 1.62 (sext.,
J = 7.5 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.6, 152.5, 149.6, 148.6, 146.1, 131.9,
126.2, 124.0, 116.3, 109.0, 41.4, 23.4, 11.8 ppm. C13H14N2O2
(230.26): calcd. C 67.81, H 6.13; found C 67.97, H 6.14.
1
afforded 33b in 66% (0.212 g) yield. H NMR (300 MHz, CDCl3):
δ = 9.99 (s, 1 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 2
H), 7.50 (d, J = 5.0 Hz, 1 H), 7.30–7.22 (m, 3 H), 7.15–7.05 (m, 3
H), 5.80–5.75 (m, 1 H), 4.43 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 190.4, 160.8, 140.3, 139.8, 136.2, 134.8,
134.1, 129.1, 129.0, 128.7, 127.7, 126.8, 126.6, 43.1 ppm.
C19H15NO2S (321.39): calcd. C 71.00, H 4.70; found C 70.89, H
4.87.
Furan-2-carboxylic Acid (2-Methoxyethyl)amide (25): The reaction
of furan-2-carbonyl chloride (0.312 g, 2.4 mmol) and 2-methoxy-
ethylamine (0.150 g, 2 mmol) in triethylamine (4 mL) and dichloro-
methane (30 mL) at room temperature over 3 h gave 25 in 70%
(0.237 g) yield after addition of an H2O/HCl solution, extraction 5-(4-Cyanophenyl)thiophene-2-carboxylic Acid Benzylamide (34): 4-
with dichloromethane, drying (MgSO4), and purification by silica
gel column chromatography. 1H NMR (300 MHz, CDCl3): δ =
7.30–7.25 (m, 1 H), 7.00–6.80 (m, 2 H), 6.30–6.20 (m, 1 H), 3.50–
Bromobenzonitrile (0.182 g, 1 mmol) and 32 (0.325 g, 1.5 mmol)
afforded 34 in 72% (0.229 g) yield. H NMR (300 MHz, CDCl3):
1
δ = 7.80–7.25 (m, 11 H), 6.40–6.20 (m, 1 H), 4.65 (d, J = 5.7 Hz, 2
3.30 (m, 4 H), 3.18 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 158.2, 143.0, 139.0,
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4381

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
137.4, 135.5, 131.4, 127.7, 126.7, 125.7, 125.3, 125.2, 124.7, 117.3,
109.4, 43.4 ppm. C19H14N2OS (318.39): calcd. C 71.67, H 4.43;
found C 71.80, H 4.52.
6.40–6.20 (m, 1 H), 6.05 (m, 1 H), 4.56 (d, J = 5.7 Hz, 2 H), 3.92
(s, 3 H) ppm.
5-(4-Cyanophenyl)-1-methylpyrrole-2-carboxylic Acid Benzylamide
(44): 4-Bromobenzonitrile (0.182 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 44 in 75% (0.236 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.70 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H),
7.40–7.20 (m, 5 H), 6.56 (d, J = 3.7 Hz, 1 H), 6.50–6.40 (m, 1 H),
6.22 (d, J = 3.7 Hz, 1 H), 4.55 (d, J = 5.7 Hz, 2 H), 3.88 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.8, 138.5, 138.0,
136.8, 132.3, 129.5, 128.8, 128.7, 127.7, 127.5, 118.7, 111.9, 111.1,
109.8, 43.4, 34.7 ppm. C20H17N3O (315.37): calcd. C 76.17, H 5.43;
found C 76.40, H 5.29.
Methyl 4-(5-Benzylcarbamoylthiophen-2-yl)benzoate (35): Methyl 4-
bromobenzoate (0.215 g, 1 mmol) and 32 (0.325 g, 1.5 mmol) af-
1
forded 35 in 81% (0.284 g) yield. H NMR (300 MHz, CDCl3): δ
= 8.11 (d, J = 8.4 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 7.48 (d, J =
3.7 Hz, 1 H), 7.40–7.20 (m, 6 H), 6.40–6.20 (m, 1 H), 4.71 (d, J =
5.7 Hz, 2 H), 3.91 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 165.1, 160.1, 145.1, 139.7, 138.7, 136.8, 129.5, 128.7, 128.4,
127.7, 126.6, 126.3, 125.4, 125.1, 51.6, 41.9 ppm. C20H17NO3S
(351.42): calcd. C 68.36, H 4.88; found C 68.22, H 4.71.
Methyl 4-(5-Benzylcarbamoyl-1-methylpyrrol-2-yl)benzoate (45):
Methyl 4-bromobenzoate (0.215 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 45 in 73% (0.254 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.08 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H),
7.40–7.20 (m, 5 H), 6.57 (d, J = 3.7 Hz, 1 H), 6.50–6.30 (m, 1 H),
6.22 (d, J = 3.7 Hz, 1 H), 4.57 (d, J = 5.7 Hz, 2 H), 3.88 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 161.9, 139.0,
138.6, 136.7, 129.7, 129.2, 129.0, 128.7, 128.0, 127.7, 127.5, 111.7,
109.3, 52.2, 43.4, 34.7 ppm. C21H20N2O3 (348.40): calcd. C 72.40,
H 5.79; found C 72.38, H 5.87.
5-(4-Fluorophenyl)thiophene-2-carboxylic Acid Benzylamide (36): 4-
Bromofluorobenzene (0.175 g, 1 mmol) and 32 (0.325 g, 1.5 mmol)
afforded 36 in 66% (0.205 g) yield. H NMR (300 MHz, CDCl3):
δ = 7.55 (dd, J = 8.4, 5.2 Hz, 2 H), 7.48 (d, J = 3.7 Hz, 1 H), 7.40–
7.25 (m, 5 H), 7.17 (d, J = 3.7 Hz, 1 H), 7.10 (t, J = 8.4 Hz, 2 H),
6.60–6.40 (m, 1 H), 4.62 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.8 (d, J = 248.9 Hz), 160.6, 146.8, 136.9,
136.3, 128.0, 127.8, 127.0, 126.9, 126.7 (d, J = 3.6 Hz), 122.4, 115.1
(d, J = 22.0 Hz), 43.0 ppm. C18H14FNOS (311.37): calcd. C 69.43,
H 4.53; found C 69.20, H 4.40.
1
5-(3-Formylphenyl)-1-methylpyrrole-2-carboxylic Acid Benzylamide
(46): 3-Bromobenzaldehyde (0.185 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 46 in 48% (0.151 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 10.03 (s, 1 H), 7.88 (s, 1 H), 7.84 (d, J = 8.0 Hz, 1 H),
7.70–7.50 (m, 2 H), 7.40–7.20 (m, 5 H), 6.60 (d, J = 3.7 Hz, 1 H),
6.40–6.30 (m, 1 H), 6.19 (d, J = 3.7 Hz, 1 H), 4.57 (d, J = 5.7 Hz,
2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.9,
161.9, 138.6, 138.5, 136.7, 134.9, 133.4, 130.3, 129.2, 128.9, 128.7,
127.7, 127.5, 111.7, 109.0, 43.4, 34.5 ppm. C20H18N2O2 (318.37):
calcd. C 75.45, H 5.70; found C 75.44, H 5.57.
5-(3-Acetylphenyl)thiophene-2-carboxylic Acid Benzylamide (37): 3-
Bromoacetophenone (0.199 g, 1 mmol) and 32 (0.325 g, 1.5 mmol)
afforded 37 in 72% (0.241 g) yield. H NMR (300 MHz, CDCl3):
δ = 8.18 (s, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1
H), 7.60–7.20 (m, 8 H), 6.50–6.30 (m, 1 H), 4.63 (d, J = 5.7 Hz, 2
H), 2.64 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.6,
160.5, 146.6, 137.1, 136.9, 136.8, 133.0, 129.4, 128.4, 128.0, 127.8,
127.2, 126.9, 126.7, 124.6, 123.2, 43.0, 25.7 ppm. C20H17NO2S
(335.42): calcd. C 71.62, H 5.11; found C 71.39, H 5.20.
1
5-(2-Cyanophenyl)thiophene-2-carboxylic Acid Benzylamide (38): 2-
Bromobenzonitrile (0.182 g, 1 mmol) and 32 (0.325 g, 1.5 mmol)
1-Methyl-5-(3-trifluoromethylphenyl)pyrrole-2-carboxylic
Acid
Benzylamide (47): 3-(Trifluoromethyl)bromobenzene (0.225 g,
1 mmol) and 43 (0.321 g, 1.5 mmol) afforded 47 in 70% (0.251 g)
1
afforded 38 in 71% (0.226 g) yield. H NMR (300 MHz, CDCl3):
δ = 7.80–7.25 (m, 11 H), 6.70–6.50 (m, 1 H), 4.62 (d, J = 5.7 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.8, 144.1, 140.7,
138.3, 137.0, 134.8, 133.7, 130.2, 129.2, 128.9, 128.8, 128.4, 128.3,
128.1, 118.9, 110.6, 44.5 ppm. C19H14N2OS (318.39): calcd. C
71.67, H 4.43; found C 71.78, H 4.32.
1
yield. H NMR (300 MHz, CDCl3): δ = 7.80–7.20 (m, 9 H), 6.67
(d, J = 3.7 Hz, 1 H), 6.41 (t, J = 5.7 Hz, 1 H), 6.23 (d, J = 3.7 Hz,
1 H), 4.62 (d, J = 5.7 Hz, 2 H), 3.92 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 162.7, 139.4, 139.3, 133.9, 133.2, 131.8 (q,
J = 32.0 Hz), 129.8, 129.6, 128.5, 128.3, 126.7 (q, J = 3.8 Hz), 125.5
(q, J = 3.8 Hz), 125.0 (q, J = 272.0 Hz), 112.5, 109.8, 44.1,
35.3 ppm. C20H17F3N2O (358.36): calcd. C 67.03, H 4.78; found C
67.11, H 4.64.
5-(2-Trifluoromethylphenyl)thiophene-2-carboxylic
Acid
Benz-
ylamide (39):[20] 2-(Trifluoromethyl)bromobenzene (0.225 g,
1 mmol) and 32 (0.325 g, 1.5 mmol) afforded 39 in 75% (0.271 g)
1
yield. H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 6.8 Hz, 1 H),
5-(3-Cyanophenyl)-1-methylpyrrole-2-carboxylic Acid Benzylamide
(48): 3-Bromobenzonitrile (0.182 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 48 in 76% (0.239 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.70–7.50 (m, 4 H), 7.40–7.20 (m, 5 H), 6.61 (d, J =
3.7 Hz, 1 H), 6.50–6.30 (m, 1 H), 6.18 (d, J = 3.7 Hz, 1 H), 4.55 (d,
J = 5.7 Hz, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 161.8, 138.5, 137.4, 133.7, 133.4, 132.5, 131.2, 129.4, 128.7, 128.1,
127.7, 127.5, 118.4, 112.9, 111.8, 109.3, 43.4, 34.5 ppm. C20H17N3O
(315.37): calcd. C 76.17, H 5.43; found C 76.04, H 5.49.
7.65–7.15 (m, 9 H), 7.07 (d, J = 3.5 Hz, 1 H), 6.79 (t, J = 5.7 Hz,
1 H), 4.62 (d, J = 5.7 Hz, 2 H) ppm.
5-Pyridin-4-ylthiophene-2-carboxylic Acid Benzylamide (40): 4-Bro-
mopyridine hydrochloride (0.194 g, 1 mmol) and 32 (0.325 g,
1.5 mmol) afforded 40 in 78% (0.229 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.60 (d, J = 4.9 Hz, 2 H), 7.60–7.15 (m, 9 H), 6.80–
6.75 (m, 1 H), 4.63 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 161.0, 150.9, 144.5, 141.5, 140.3, 139.6, 129.6,
128.7, 127.7, 127.4, 127.3, 120.1, 43.0 ppm. C17H14N2OS (294.37):
calcd. C 69.36, H 4.79; found C 69.20, H 4.82.
5-(2-Cyanophenyl)-1-methylpyrrole-2-carboxylic Acid Benzylamide
(49): 2-Bromobenzonitrile (0.182 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 49 in 72% (0.227 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.77 (d, J = 7.6 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H),
7.55–7.20 (m, 7 H), 6.70 (d, J = 4.0 Hz, 1 H), 6.59 (t, J = 5.7 Hz,
1 H), 6.37 (d, J = 4.0 Hz, 1 H), 4.59 (d, J = 5.7 Hz, 2 H), 3.85 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.3, 139.0, 136.2,
135.4, 133.9, 132.9, 131.7, 129.1, 128.8, 128.4, 128.1, 127.8, 118.5,
113.7, 112.1, 111.0, 43.7, 34.8 ppm. C20H17N3O (315.37): calcd. C
76.17, H 5.43; found C 76.27, H 5.57.
1-Methylpyrrole-2-carboxylic Acid Benzylamide (43):[24] The reac-
tion of 1-methylpyrrole-2-carbonyl chloride (0.343 g, 2.4 mmol)
and benzylamine (0.214 g, 2 mmol) in triethylamine (4 mL) and
dichloromethane (30 mL) at room temperature over 3 h gave 43 in
66% (0.282 g) yield after addition of an H2O/HCl solution, extrac-
tion with dichloromethane, drying (MgSO4), and purification by
1
silica gel column chromatography. H NMR (300 MHz, CDCl3): δ
= 7.50–7.30 (m, 5 H), 6.71 (m, 1 H), 6.54 (d, J = 3.7 Hz, 1 H),
4382
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
1-Methyl-5-pyridin-4-ylpyrrole-2-carboxylic Acid Benzylamide (50): J = 5.7 Hz, 2 H), 2.70 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
4-Bromopyridine hydrochloride (0.194 g, 1 mmol) and 43 (0.321 g,
1.5 mmol) afforded 50 in 78% (0.227 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.58 (d, J = 4.9 Hz, 2 H), 7.40–7.20 (m, 7 H), 6.90–
6.80 (m, 1 H), 6.62 (d, J = 3.7 Hz, 1 H), 6.24 (d, J = 3.7 Hz, 1 H),
4.55 (d, J = 5.7 Hz, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 161.8, 149.7, 140.2, 138.6, 136.7, 129.2, 128.7, 127.6,
127.4, 123.3, 112.1, 110.0, 43.3, 34.7 ppm. C18H17N3O (291.35):
calcd. C 74.20, H 5.88; found C 74.27, H 6.07.
δ = 163.6, 162.3 (d, J = 247.5 Hz), 156.5, 150.9, 138.3, 128.8, 128.0,
127.6, 125.4 (d, J = 8.0 Hz), 126.3 (d, J = 3.2 Hz), 117.2, 115.8 (d,
J = 22.0 Hz), 102.8, 43.5, 13.7 ppm. C19H16FNO2 (309.33): calcd.
C 73.77, H 5.21; found C 73.64, H 5.21.
2-Methyl-5-(3-nitrophenyl)furan-3-carboxylic Acid Benzylamide
(57): 3-Bromonitrobenzene (0.202 g, 1 mmol) and 52 (0.323 g,
1.5 mmol) afforded 57 in 72% (0.242 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.39 (s, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.88 (d, J =
1-Methyl-5-pyridin-3-ylpyrrole-2-carboxylic Acid Benzylamide (51): 8.1 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.40–7.25 (m, 5 H), 6.92 (s,
3-Bromopyridine (0.158 g, 1 mmol) and 43 (0.321 g, 1.5 mmol) af-
forded 51 in 74% (0.215 g) yield. H NMR (300 MHz, CDCl3): δ
= 8.59 (s, 1 H), 8.53 (d, J = 4.0 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1
1 H), 6.60–6.50 (m, 1 H), 4.60 (d, J = 5.7 Hz, 2 H), 2.70 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.3, 157.7, 149.1,
148.7, 138.3, 131.5, 129.8, 128.9, 128.7, 127.8, 127.5, 121.9, 118.3,
1
H), 7.40–7.00 (m, 6 H), 6.95–6.85 (m, 1 H), 6.71 (d, J = 3.9 Hz, 1 117.9, 105.7, 43.5, 13.8 ppm. C19H16N2O4 (336.34): calcd. C 67.85,
H), 6.17 (d, J = 3.9 Hz, 1 H), 4.55 (d, J = 5.7 Hz, 2 H), 3.88 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.9, 148.7, 147.6,
137.7, 135.3, 135.1, 127.6, 127.3, 127.0, 126.5, 126.2, 122.2, 110.9,
108.1, 42.1, 33.3 ppm. C18H17N3O (291.35): calcd. C 74.20, H 5.88;
found C 74.34, H 6.01.
H 4.79; found C 67.69, H 4.89.
5-(2-Cyanophenyl)-2-methylfuran-3-carboxylic Acid Benzylamide
(58): 2-Bromobenzonitrile (0.182 g, 1 mmol), 52 (0.323 g,
1.5 mmol) afforded 58 in 85% (0.269 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.87 (d, J = 8.2 Hz, 1 H), 7.70–7.55 (m, 2 H), 7.40–
7.25 (m, 7 H), 6.60–6.50 (m, 1 H), 4.60 (d, J = 5.7 Hz, 2 H), 2.72
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.2, 157.1, 146.1,
137.4, 133.1, 132.0, 131.3, 127.6, 126.7, 126.3, 126.2, 124.6, 117.9,
116.8, 107.4, 105.2, 42.3, 12.7 ppm. C20H16N2O2 (316.35): calcd. C
75.93, H 5.10; found C 75.98, H 4.95.
2-Methylfuran-3-carboxylic Acid Benzylamide (52):[25] The reaction
of 2-methyl-3-furoyl chloride (0.347 g, 2.4 mmol) and benzylamine
(0.214 g, 2 mmol) in triethylamine (4 mL) and dichloromethane
(30 mL) at room temperature over 3 h gave 52 in 73% (0.314 g)
yield after addition of an H2O/HCl solution, extraction with
dichloromethane, drying (MgSO4), and purification by silica gel
2-Methyl-5-pyridin-3-ylfuran-3-carboxylic Acid Benzylamide (59): 3-
Bromopyridine (0.158 g, 1 mmol) and 52 (0.323 g, 1.5 mmol) af-
forded 59 in 78% (0.228 g) yield. H NMR (300 MHz, CDCl3): δ
= 8.70 (s, 1 H), 8.35–8.30 (m, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.40–
7.00 (m, 7 H), 6.92 (s, 1 H), 4.51 (d, J = 5.7 Hz, 2 H), 2.61 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.2, 157.1, 147.8,
147.5, 144.3, 138.1, 130.2, 128.1, 127.7, 126.8, 125.8, 124.0, 117.3,
1
column chromatography. H NMR (300 MHz, CDCl3): δ = 7.40–
7.20 (m, 5 H), 7.14 (d, J = 2.1 Hz, 1 H), 6.60–6.50 (m, 1 H), 6.44
(d, J = 2.1 Hz, 1 H), 4.56 (d, J = 5.8 Hz, 2 H), 2.62 (s, 3 H) ppm.
1
5-(4-Formylphenyl)-2-methylfuran-3-carboxylic Acid Benzylamide
(53): 4-Bromobenzaldehyde (0.185 g, 1 mmol) and 52 (0.323 g,
1.5 mmol) afforded 53 in 68% (0.217 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 9.91 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 104.8, 42.9, 13.3 ppm. C18H16N2O2 (292.33): calcd. C 73.95, H
8.4 Hz, 2 H), 7.40–7.25 (m, 5 H), 6.88 (s, 1 H), 6.60–6.40 (m, 1 H),
4.68 (d, J = 5.7 Hz, 2 H), 2.68 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 191.5, 163.3, 158.0, 150.2, 138.3, 135.3, 135.0, 130.3,
128.7, 127.8, 127.5, 123.7, 118.0, 106.5, 43.5, 13.8 ppm. C20H17NO3
(319.35): calcd. C 75.22, H 5.37; found C 75.04, H 5.31.
5.52; found C 74.07, H 5.41.
1-Ethyl-3-methylpyrazole-5-carboxylic Acid Benzylamide (63): The
reaction of 1-ethyl-3-methylpyrazole-5-carbonyl chloride (0.413 g,
2.4 mmol) and benzylamine (0.214 g, 2 mmol) in triethylamine
(4 mL) and dichloromethane (30 mL) at room temperature over 3 h
5-(4-Cyanophenyl)-2-methylfuran-3-carboxylic Acid Benzylamide gave 63 in 70% (0.340 g) yield after addition of an H2O/HCl solu-
(54): 4-Bromobenzonitrile (0.182 g, 1 mmol) and 52 (0.323 g,
1.5 mmol) afforded 54 in 78% (0.247 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.64 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H),
7.40–7.25 (m, 5 H), 6.89 (s, 1 H), 6.60–6.40 (m, 1 H), 4.68 (d, J =
5.7 Hz, 2 H), 2.68 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
163.1, 158.1, 149.6, 138.2, 133.8, 132.6, 128.8, 127.8, 127.6, 123.7,
118.8, 118.0, 110.6, 106.5, 43.5, 13.8 ppm. C20H16N2O2 (316.35):
calcd. C 75.93, H 5.10; found C 75.89, H 4.98.
tion, extraction with dichloromethane, drying (MgSO4), and purifi-
cation by silica gel column chromatography. H NMR (300 MHz,
1
CDCl3): δ = 7.30–7.20 (m, 6 H), 6.29 (s, 1 H), 4.50–4.40 (m, 4 H),
2.15 (s, 3 H), 1.33 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.1, 146.7, 138.0, 135.1, 128.6, 127.5, 127.4, 106.2,
46.2, 43.2, 16.0, 13.2 ppm. C14H17N3O (243.30): calcd. C 69.11, H
7.04; found C 68.89, H 7.14.
4-(4-Cyanophenyl)-1-ethyl-3-methylpyrazole-5-carboxylic
Acid
Methyl 4-(4-Benzylcarbamoyl-5-methylfuran-2-yl)benzoate (55):
Benzylamide (64): 4-Bromobenzonitrile (0.182 g, 1 mmol) and 63
Methyl 4-bromobenzoate (0.215 g, 1 mmol) and 52 (0.323 g, (0.365 g, 1.5 mmol) afforded 64 in 78% (0.268 g) yield. 1H NMR
1.5 mmol) afforded 55 in 67% (0.234 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.05 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.4 Hz, 2 H),
7.40–7.25 (m, 5 H), 6.84 (s, 1 H), 6.50–6.30 (m, 1 H), 4.61 (d, J =
5.7 Hz, 2 H), 3.91 (s, 3 H), 2.70 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.7, 163.4, 157.6, 150.6, 138.3, 133.9, 130.1, 128.8,
128.7, 127.8, 127.6, 123.2, 117.8, 105.5, 52.1, 43.5, 13.8 ppm.
C21H19NO4 (349.38): calcd. C 72.19, H 5.48; found C 72.31, H
5.57.
(300 MHz, CDCl3): δ = 7.47 (d, J = 8.4 Hz, 2 H), 7.30–7.10 (m, 5
H), 7.05–6.90 (m, 2 H), 5.75 (m, 1 H), 4.42 (q, J = 7.5 Hz, 2 H),
4.38 (d, J = 6.2 Hz, 2 H), 2.17 (s, 3 H), 1.44 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.8, 144.1, 136.2,
135.8, 132.8, 131.4, 129.3, 127.7, 126.9, 126.8, 117.9, 117.4, 109.9,
45.3, 42.7, 15.0, 11.1 ppm. C21H20N4O (344.41): calcd. C 73.23, H
5.85; found C 73.42, H 5.74.
4-(4-Formylphenyl)-1-ethyl-3-methylpyrazole-5-carboxylic
Acid
5-(4-Fluorophenyl)-2-methylfuran-3-carboxylic Acid Benzylamide Benzylamide (65): 4-Bromobenzaldehyde (0.185 g, 1 mmol) and 63
1
(56): 4-Bromofluorobenzene (0.175 g, 1 mmol) and 52 (0.323 g,
1.5 mmol) afforded 56 in 71% (0.219 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 7.62 (dd, J = 8.4, 5.2 Hz, 2 H), 7.40–7.25 (m, 5 H),
7.14 (t, J = 8.4 Hz, 2 H), 6.55 (s, 1 H), 6.20–6.00 (m, 1 H), 4.65 (d,
(0. 365 g, 1.5 mmol) afforded 65 in 76% (0.264 g) yield. H NMR
(300 MHz, CDCl3): δ = 9.93 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2 H),
7.35 (d, J = 8.4 Hz, 2 H), 7.25–7.15 (m, 3 H), 7.00–6.90 (m, 2 H),
5.83 (m, 1 H), 4.46 (q, J = 7.5 Hz, 2 H), 4.36 (d, J = 6.2 Hz, 2 H),
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4383

N. Laidaoui, J. Roger, A. Miloudi, D. El Abed, H. Doucet
FULL PAPER
2.17 (s, 3 H), 1.46 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 191.5, 159.9, 145.3, 138.7, 136.8, 135.1, 133.6, 130.3,
130.0, 128.7, 127.8, 127.7, 119.5, 46.4, 43.7, 16.0, 12.1 ppm.
C21H21N3O2 (347.41): calcd. C 72.60, H 6.09; found C 72.51, H
6.01.
York, 2002, part III, p. 213; c) J. Hassan, M. Sévignon, C.
Gozzi, E. Schultz, M. Lemaire, Chem. Rev. 2002, 102, 1359; d)
I. Kondolff, H. Doucet, M. Santelli, Synlett 2005, 2057.
a) Y. Akita, A. Inoue, K. Yamamoto, A. Ohta, T. Kurihara,
M. Shimizu, Heterocycles 1985, 23, 2327; b) A. Ohta, Y. Akita,
T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji, T. Nakata,
N. Tani, Y. Aoyagi, Heterocycles 1990, 31, 1951.
a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174; b) T. Satoh, M. Miura, Chem. Lett. 2007, 36, 200; c) L.-
C. Campeau, D. R. Stuart, K. Fagnou, Aldrichimica Acta 2007,
40, 35; d) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,
36, 1173; e) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949; f)
F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269; g) L. Acker-
mann, R. Vicente, A. Kapdi, Angew. Chem. 2009, 121, 9976;
Angew. Chem. Int. Ed. 2009, 48, 9792; h) J. Roger, A. L. Gottu-
mukkala, H. Doucet, ChemCatChem 2010, 2, 20; i) C.-L. Sun,
B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677; j) C. Fisch-
meister, H. Doucet, Green Chem. 2011, 13, 741.
[3]
[4]
1-Ethyl-3-methyl-4-(3-nitrophenyl)pyrazole-5-carboxylic Acid Benz-
ylamide (66): 3-Bromonitrobenzene (0.202 g, 1 mmol) and 63 (0.
365 g, 1.5 mmol) afforded 66 in 82% (0.299 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 8.05 (m, 2 H), 7.50 (d, J = 8.2 Hz, 1 H),
7.44 (t, J = 7.6 Hz, 1 H), 7.25–7.15 (m, 3 H), 7.05–6.95 (m, 2 H),
5.79 (m, 1 H), 4.37 (q, J = 7.5 Hz, 2 H), 4.35 (d, J = 6.2 Hz, 2 H),
2.17 (s, 3 H), 1.45 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.8, 148.3, 145.3, 136.8, 135.8, 134.1, 133.7, 129.7,
128.7, 127.7, 127.6, 124.3, 122.2, 118.3, 46.4, 43.7, 16.0, 12.0 ppm.
C20H20N4O3 (364.40): calcd. C 65.92, H 5.53; found C 65.87, H
5.41.
[5]
For selected recent examples of palladium-catalyzed direct aryl-
ations of pyrroles, indoles, or imidazoles, see: a) F. Bellina, S.
Cauteruccio, R. Rossi, Eur. J. Org. Chem. 2006, 1379; b) F.
Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel, Eur. J.
Org. Chem. 2006, 693; c) I. Cerna, R. Pohl, B. Klepetarova, M.
Hocek, Org. Lett. 2006, 8, 5389; d) F. Bellina, C. Calandri, S.
Cauteruccio, R. Rossi, Tetrahedron 2007, 63, 1970; e) N. Leb-
rasseur, I. Larrosa, J. Am. Chem. Soc. 2008, 130, 2926; f) F.
Bellina, S. Cauteruccio, A. Di Flore, R. Rossi, Eur. J. Org.
Chem. 2008, 5436; g) F. Bellina, S. Cauteruccio, A. Di Flore,
C. Marchietti, R. Rossi, Tetrahedron 2008, 64, 6060; h) S.-D.
Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew.
Chem. 2008, 120, 1495; Angew. Chem. Int. Ed. 2008, 47, 1473;
i) Y. Fall, H. Doucet, M. Santelli, ChemSusChem 2009, 2, 153;
j) F. Jafarpour, S. Rahiminejadan, H. Hazrati, J. Org. Chem.
2010, 75, 3109; k) J. Roger, H. Doucet, Tetrahedron 2009, 65,
9772.
For recent examples of palladium-catalyzed direct 2- or 5-aryl-
ations of thiazoles or oxazoles, see: a) C. Hoarau, A.
Du Fou de Kerdaniel, N. Bracq, P. Grandclaudon, A. Couture,
F. Marsais, Tetrahedron Lett. 2005, 46, 8573; b) see ref.[5a]; c)
R. S. Sanchez, F. A. Zhuravlev, J. Am. Chem. Soc. 2007, 129,
5824; d) A. L. Gottumukkala, H. Doucet, Eur. J. Inorg. Chem.
2007, 3629; e) L.-C. Campeau, M. Bertrand-Laperle, J.-P. Le-
clerc, E. Villemure, S. Gorelsky, K. Fagnou, J. Am. Chem. Soc.
2008, 130, 3276; f) T. Martin, C. Verrier, C. Hoarau, F. Mar-
sais, Org. Lett. 2008, 10, 2909; g) F. Besselievre, F. Mahuteau-
Betzer, D. S. Grierson, S. Piguel, J. Org. Chem. 2008, 73, 3278;
h) C. Verrier, T. Martin, C. Hoarau, F. Marsais, J. Org. Chem.
2008, 73, 7383; i) J. Roger, F. Pozˇgan, H. Doucet, J. Org. Chem.
2009, 74, 1179; j) T. Yoshizumi, T. Satoh, K. Hirano, D. Mat-
suo, A. Orita, J. Otera, M. Miura, Tetrahedron Lett. 2009, 50,
3273; k) F. Derridj, J. Roger, S. Djebbar, H. Doucet, J. Or-
ganomet. Chem. 2009, 694, 455; l) C. Verrier, C. Hoarau, F.
Marsais, Org. Biomol. Chem. 2009, 7, 647; m) J. Roger, C. Verr-
ier, R. Le Goff, C. Hoarau, H. Doucet, ChemSusChem 2009,
2, 951; n) D. Roy, S. Mom, M. Beaupérin, H. Doucet, J.-C.
Hierso, Angew. Chem. Int. Ed. 2010, 49, 6650.
1-Ethyl-3-methyl-4-(3-trifluoromethylphenyl)pyrazole-5-carboxylic
Acid Benzylamide (67): 3-(Trifluoromethyl)bromobenzene (0.225 g,
1 mmol) and 63 (0. 365 g, 1.5 mmol) afforded 67 in 71% (0.275 g)
1
yield. H NMR (300 MHz, CDCl3): δ = 7.60–7.20 (m, 7 H), 7.05–
6.95 (m, 2 H), 5.60 (m, 1 H), 4.59 (q, J = 7.5 Hz, 2 H), 4.38 (d, J
= 6.2 Hz, 2 H), 2.18 (s, 3 H), 1.46 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.3, 145.8, 137.2, 133.7, 133.4,
131.8 (q, J = 32.5 Hz), 129.9, 129.1, 128.1, 127.9, 126.9 (q, J =
3.7 Hz), 125.0 (q, J = 272.0 Hz), 124.8 (q, J = 3.8 Hz), 119.7, 106.0,
47.0, 44.1, 16.5, 12.4 ppm. C21H20F3N3O (387.40): calcd. C 65.11,
H 5.20; found C 65.19, H 5.01.
4-(2-Cyanophenyl)-1-ethyl-3-methylpyrazole-5-carboxylic
Acid
Benzylamide (68): 2-Bromobenzonitrile (0.182 g, 1 mmol) and 63
1
(0. 365 g, 1.5 mmol) afforded 68 in 80% (0.275 g) yield. H NMR
(300 MHz, CDCl3): δ = 7.63 (d, J = 8.2 Hz, 1 H), 7.50 (t, J =
7.6 Hz, 1 H), 7.45–7.15 (m, 5 H), 7.00–6.95 (m, 2 H), 5.66 (m, 1
H), 4.55–4.35 (m, 4 H), 2.14 (s, 3 H), 1.48 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 158.4, 144.8, 135.9, 135.2, 132.9,
132.3, 132.0, 130.8, 127.6, 127.2, 126.6, 126.5, 116.6, 116.0, 112.7,
45.6, 42.6, 15.0, 11.0 ppm. C21H20N4O (344.41): calcd. C 73.23, H
5.85; found C 73.40, H 5.97.
[6]
1-Ethyl-3-methyl-4-pyridin-3-ylpyrazole-5-carboxylic Acid Benz-
ylamide (69): 3-Bromopyridine (0.158 g, 1 mmol) and 63 (0. 365 g,
1.5 mmol) afforded 69 in 74% (0.237 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.50–8.00 (m, 2 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.30–
7.00 (m, 6 H), 6.00 (m, 1 H), 4.45 (q, J = 7.5 Hz, 2 H), 4.41 (d, J
= 6.2 Hz, 2 H), 2.19 (s, 3 H), 1.46 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.2, 148.8, 146.9, 144.3, 136.3,
133.2, 127.6, 126.8, 126.6, 122.5, 115.7, 45.3, 42.7, 15.0, 11.1 ppm.
C19H20N4O (320.39): calcd. C 71.23, H 6.29; found C 70.47, H
6.18.
Acknowledgments
[7]
For recent examples of palladium-catalyzed direct arylations of
thiophenes, see: a) E. David, S. Pellet-Rostaing, M. Lemaire,
Tetrahedron 2007, 63, 8999; b) H. A. Chiong, O. Daugulis, Org.
Lett. 2007, 9, 1449; c) P. Amaladass, J. A. Clement, A. K. Mo-
hanakrishnan, Tetrahedron 2007, 63, 10363; d) F. Derridj, A. L.
Gottumukkala, S. Djebbar, H. Doucet, Eur. J. Inorg. Chem.
2008, 2550; e) M. Nakano, H. Tsurugi, T. Satoh, M. Miura,
Org. Lett. 2008, 10, 1851; f) J. J. Dong, J. Roger, H. Doucet,
Tetrahedron Lett. 2009, 50, 2778; g) J. J. Dong, J. Roger, C.
Verrier, T. Martin, R. Le Goff, C. Hoarau, H. Doucet, Green
Chem. 2010, 12, 2053; h) B. Liegault, I. Petrov, S. I. Gorelsky,
K. Fagnou, J. Org. Chem. 2010, 75, 1047; i) F. Derridj, J. Roger,
S. Djebbar, H. Doucet, Org. Lett. 2010, 12, 4320; j) J. J. Dong,
H. Doucet, Eur. J. Org. Chem. 2010, 611.
We thank the Centre National de la Recherche Scientifique
(CNRS) and “Rennes Metropole” for providing financial support.
[1] a) P. M. Shah, Chemother. J. 2005, 14, 35; b) H. M. Colhoun,
D. J. Betteridge, P. N. Durrington, G. A. Hitman, H. A. Wneil,
S. J. Livingstone, M. J. Thomason, M. I. MacKness, V.
Charlton-Menys, J. H. Fuller, Lancet 2004, 364, 685; c) A. J.
Scheen, N. Finer, P. Hollander, M. D. Jensen, L. F Van Gaal,
Lancet 2006, 368,1660.
[2] a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry,
Pergamon, Amsterdam, 2000; b) E. Negishi (Ed.), Handbook of
Organopalladium Chemistry for Organic Synthesis, Wiley, New
4384
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4373–4385

Palladium-Catalyzed Direct Arylations of Five-Membered Heteroarenes
[8]
[14] For examples of palladium-catalyzed direct arylations using
For recent examples of palladium-catalyzed direct arylations of
furans, see: a) M. Parisien, D. Valette, K. Fagnou, J. Org.
Chem. 2005, 70, 7578; b) T. A. Dwight, N. R. Rue, D. Charyk,
R. Josselyn, B. DeBoef, Org. Lett. 2007, 9, 3137; c) E. M.
Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Synthesis
2008, 136; d) A. L. Gottumukkala, H. Doucet, Adv. Synth. Ca-
tal. 2008, 350, 2183; e) R. V. Smaliy, M. Beaupérin, H. Cattey,
P. Meunier, J.-C. Hierso, J. Roger, H. Doucet, Y. Coppel, Orga-
nometallics 2009, 28, 3152; f) B. Liégaut, D. Lapointe, L. Ca-
ron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826; g)
M. Ionita, J. Roger, H. Doucet, ChemSusChem 2010, 3, 367; h)
J. Roger, F. Pozgan, H. Doucet, Adv. Synth. Catal. 2010, 352,
696.
a) T. Okazawa, T. Satoh, M. Miura, M. Nomura, J. Am. Chem.
Soc. 2002, 124, 5286; b) A. Yokooji, T. Okazawa, T. Satoh, M.
Miura, M. Nomura, Tetrahedron 2003, 59, 5685; c) M. Nak-
ano, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1851.
For examples of palladium-catalyzed direct arylations using 2-
furamide derivatives, see: L.-C. Campeau, M. Parisien, A. Jean,
K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581.
thiophene 2-carboxylates, see: J. Roger, F. Pozgan, H. Doucet,
ˇ
Green Chem. 2009, 11, 425; and ref.[12b]
[15] D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118.
[16] For examples of palladium-catalyzed direct arylations using
pyrrole 2-carboxylates, see: a) X. Wang, D. V. Gribkov, D.
Sames, J. Org. Chem. 2007, 72, 1476; b) J. Roger, H. Doucet,
Adv. Synth. Catal. 2009, 351, 1977; and ref.[12b]
[17] For examples of palladium-catalyzed direct arylations using
pyrazole carboxylates, see: a) R. Goikhman, T. L. Jacques, D.
Sames, J. Am. Chem. Soc. 2009, 131, 3042; b) Y. Fall, H. Dou-
cet, M. Santelli, Synthesis 2010, 127.
[18] A. Padwa, K. R. Crawford, C. S. Straub, S. N. Pieniazek, K. N.
Houk, J. Org. Chem. 2006, 71, 5432.
[9]
[19] R. A. Scheuerman, D. Tumelty, Tetrahedron Lett. 2000, 41,
6531.
[20] P. Vedantham, M. Zhang, P. J. Gor, M. Huang, G. I. Georg,
G. H. Lushington, L. A. Mitscher, Q.-Z. Ye, P. R. Hanson, J.
Comb. Chem. 2008, 10, 195.
[10]
[21] C. Yamagami, M. Yokota, N. Takao, J. Chromatogr. A 1994,
662, 49.
[11] For examples of palladium-catalyzed direct arylations using
thiophenes substituted by amides, see: a) E. M. Beccalli, G.
Broggini, M. Martinelli, G. Paladino, C. Zoni, Eur. J. Org.
Chem. 2005, 2091; and ref.[10]
[12] For examples of palladium-catalyzed direct arylations using fu-
roic acid derivatives, see: a) J. J. Dong, J. Roger, F. Pozgan, H.
Doucet, Green Chem. 2009, 11, 1832; b) B. Liegault, D. Lapo-
inte, L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009,
74, 1826.
[22] F. Toda, H. Miyamoto, K. Kanemoto, K. Tanaka, Y. Takah-
ashi, Y. Takenaka, J. Org. Chem. 1999, 64, 2096.
[23] J. Blum, A. Fisher, E. Greener, Tetrahedron 1973, 29, 1073.
[24] R. Silvestri, G. La Regina, G. De Martino, M. Artico, O. Be-
fani, M. Palumbo, E. Agostinelli, P. Turini, J. Med. Chem.
2003, 46, 917.
[25] L. Fiser-Jakic, B. Karaman, K. Jakopcic, Croat. Chem. Acta
1980, 53, 69.
Received: March 4, 2011
Published Online: June 15, 2011
[13] J. Roger, H. Doucet, Eur. J. Org. Chem. 2010, 4412.
Eur. J. Org. Chem. 2011, 4373–4385
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4385