Palladium-catalysed direct 5-arylation of furfurylamine or 2-(aminoalkyl)-thiophene derivatives

Article abstract of DOI:10.1002/ejoc.201000358

The palladium-catalysed direct 5-arylation of furan or thiophene derivatives bearing CH₂NHR substituents (with. R = COMe or CO ₂tBu) generally proceeds in good yields by using a catalysts loading of only 0.1-2 mol-%. A wide range of functions such as acetyl, propionyl, formyl, ester, nitrile, trifluoromethyl or fluoro on the aryl bromide is tolerated. Higher yields were generally obtained in the presence of electron-deficient aryl bromides than with, electron-rich aryl bromides.

Full text of DOI:10.1002/ejoc.201000358

FULL PAPER
DOI: 10.1002/ejoc.201000358
Palladium-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)-
thiophene Derivatives
Julien Roger[a] and Henri Doucet*[a]
Keywords: Arylation / Heterocycles / Homogeneous catalysis / C-H activation / Palladium
The palladium-catalysed direct 5-arylation of furan or thio-
phene derivatives bearing CH2NHR substituents (with R =
COMe or CO2tBu) generally proceeds in good yields by
using a catalysts loading of only 0.1–2 mol-%. A wide range
of functions such as acetyl, propionyl, formyl, ester, nitrile,
trifluoromethyl or fluoro on the aryl bromide is tolerated.
Higher yields were generally obtained in the presence of
electron-deficient aryl bromides than with electron-rich aryl
bromides.
tuted at C2 or C3 by an amide or a carbamate have been
employed in palladium-catalysed direct intramolecular cy-
clisations.[7,8] Intermolecular direct arylation with the use of
a thiophene with a carboxanilide function at C2 was re-
ported by Miura and co-workers.[9] With this substrate, the
carbamoyl group acts as a directing group for the arylation
at the 3-position, after which it is cleaved in some cases to
give 2,3,5-triarylthiophenes (Scheme 1, left).[9a] With such
substrates, the formation of mixtures of 5-arylated and 3,5-
diarylated thiophenes has also been observed.[9b] This
group also studied the reactivity of N-phenyl-3-thiophene-
carboxamide.[9c] This reactant was successfully triarylated
at C2, C4 and C5.
Introduction
Easy access to a variety of furan or thiophene derivatives
bearing functional groups such as amino or amide is an
important field for research in organic chemistry due to the
biological properties of some of these derivatives (Figure 1).
Figure 1. Examples of bioactive furan or thiophene derivatives.
In 1990, Ohta and co-workers reported that the direct 2-
or 5-arylation of several heteroaromatics, including furans
and thiophenes, with aryl halides proceeded in moderate to
good yields by using Pd(PPh3)4 as the catalyst.[1] Since these
results, the palladium-catalysed direct arylation of het-
eroaryl derivatives with aryl halides has proved to be a very
powerful method for the synthesis of a wide variety of aryl-
ated heterocycles.[2–6] The direct arylation of quite simple
and nonreactive furan, thiophene or thiazole derivatives has
been largely described. On the other hand, heteroaromatics
bearing aminoalkyl substituents have been rarely em-
ployed.[7–12] A few furan or thiophene derivatives substi-
Scheme 1. Regioselectivity of the arylation of thiophene derivatives.
The palladium-catalysed direct 5-arylation of furfuryl-
amine or 2-(aminoalkyl)thiophene derivatives should pro-
vide a cost-effective and an environmentally attractive
method for the preparation of arylated furfurylamine or 2-
(aminoalkyl)thiophene derivatives. To the best of our
knowledge, only one example of intermolecular direct aryl-
ation of such substrates has been reported so far, and the
coupling product was obtained in 46% yield.[13] The major
byproducts of the reaction would be a base associated to
HX, instead of metallic salts produced under more classical
cross-coupling procedures[14] such as Suzuki, Negishi or
Stille reactions. The method avoids the preliminary prepa-
ration of the requisite organometallic, reducing the number
of steps to prepare these compounds. Moreover, the use of
some furan derivatives in organic synthesis, such as furfur-
[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
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Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
ylamine, which can be obtained from agricultural wastes, is observed. The formation of 3-arylated furfurylamine deriv-
an important field of research in green chemistry. Herein, ative 2d in 28% yield is probably due to the coordination
we wish to report on the use of furfurylamine or 2-(amino- of the amine to palladium.
alkyl)thiophene derivatives for palladium-catalysed direct
To avoid the formation of amides in the course of this
arylation by using a wide variety of electronically and steri- reaction, the influence of several solvents and bases was
cally diverse aryl or heteroaryl bromides at moderate to low examined (Table 1, Entries 2–12). Good conversion of 4-
catalyst loadings.
bromobenzotrifluoride was also obtained in DMF; how-
ever, the formation of formamides 2e and 2f was observed
(Table 1, Entry 2). On the other hand, in the presence of
N-methyl-2-pyrrolidone (NMP), and KOAc as the base, a
mixture of acetylated compounds 2c and 2d was obtained
Results and Discussion
To determine the reactivity of furfurylamine in the palla- (Table 1, Entry 3). Dioxane was found to be ineffective in
dium-catalysed direct arylation reactions, a set of direct promoting this coupling reaction (Table 1, Entry 4). The
arylation reactions in the presence of 4-bromobenzotrifluo- nature of the base has also a huge influence on this reac-
ride as the coupling partner, using several reaction condi- tion. K2CO3 in NMP or Cs2CO3 in DMAc led to side prod-
tions, was examined (Scheme 2, Table 1). We observed that uct 2g or 2h (Table 1, Entries 5 and 8). The use of KOH
in the presence of KOAc as the base and dimethylacetamide was also found to be ineffective (Table 1, Entries 7 and 12).
(DMAc) as the solvent with the use of PdCl(C3H5)(dppb) Moreover, with this relatively strong base, amination side
(2 mol-%) as the catalyst, compounds 2a or 2b were not product 2i was also formed.
obtained (Table 1, Entry 1). In the course of this reaction,
As the regioselective formation of 5-arylated furfuryl-
the formation of acetamides 2c and 2d in a 67:28 ratio was amines using free-NH2 furfurylamine was found to be diffi-
cult, we decided to protect this function by using either ace-
tyl or BOC substituents. First, we examined the reactivity
Table 1. Influence of the reaction conditions for the palladium-
catalysed direct coupling of furfurylamine with 4-bromobenzotri-
fluoride (Scheme 2).
of N-(furan-2-ylmethyl)acetamide (3) for the coupling with
3-bromopyridine (Scheme 3, Table 2). With this substrate,
in the presence of PdCl(C3H5)(dppb) or Pd(OAc)2 as the
catalysts, DMAc as the solvent and KOAc as the base, 5-
arylation product 4 was regioselectively obtained (Table 2,
Entries 1 and 2). The use of Pd(OAc)2 gave the highest
yield. It should be noted that the methylacetamide substitu-
ent on the furan ring does not act as a directing group for
Entry
Solvent
Base Conversion
[%][a]
Products
Product ratio
1
2
3
4
DMAc
DMF
NMP
KOAc
KOAc
KOAc
100
80
100
0
2c, 2d
2e, 2f
2c, 2d
–
67:28
47:12
37:18
–
1,4-dioxane KOAc
5
6
7
8
NMP
NMP
NMP
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
K2CO3
Na2CO3
KOH
Cs2CO3
Na2CO3 100
CsOAc
NaOAc
KOH
–
8
0
48
45
2g
–
2g, 2i
2g, 2h
–
–
21:13
19:23
9
2c, 2d, 2g, 2h, 2i 19:12:34:15:17
10
11
12
13
100
57
100
10
2c, 2d
2g, 2h
2c, 2g, 2i
2h
52:42
31:11
21:25:32
–
[a] Conditions: PdCl(C3H5)(dppb) (2 mol-%), furfurylamine
(2 equiv.), 4-bromobenzotrifluoride (1 equiv.), base (2 equiv.),
150 °C, 16 h, conversion of 4-bromobenzotrifluoride.
Scheme 3. Coupling of N-(furan-2-ylmethyl)acetamide with 3-bro-
mopyridine.
Scheme 2. Reaction of furfurylamine with 4-bromobenzotrifluoride.
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Table 2. Influence of the reaction conditions for the palladium-catalysed direct coupling of N-(furan-2-ylmethyl)acetamide with 3-bromo-
pyridine (Scheme 3).
Entry
Solvent
Base
Catalyst
T [°C]
Conversion [%][a]
Yield of 4 [%]
1
2
3
4
5
6
7
8
DMAc
DMAc
DMF
KOAc
KOAc
KOAc
KOAc
KOAc
CsOAc
NaOAc
K2CO3
Na2CO3
Cs2CO3
KOH
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
PdCl(C3H5)(dppb)
Pd(OAc)2
150
150
150
150
150
150
150
150
150
150
150
150
130
100
150
150
150
150
150
61
80
81
79
0
93
29
15
24
0
55
100
63
21
31
85
52
78
71
59
78 (71)
67
67
0
82
26
14
21
0
0
90 (80)[b]
60
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NMP
1,4-dioxane
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
9
10
11
12
13
14
15
16
17
18
19
20
31
76
50
76
69
0.5 [PdCl(C3H5)]2
Pd(OAc)2/2 PPh3
Pd(OAc)2/dppm
Pd(OAc)2/dppe
Pd(OAc)2/dppb
[a] Conditions: [Pd] (0.1 mol-%), N-(furan-2-ylmethyl)acetamide (2 equiv.), 3-bromopyridine (1 equiv.), base (2 equiv.), 16 h, conversion
of 3-bromopyridine, GC and NMR yields, yields in parenthesis are isolated yields. [b] Pd(OAc)2: 0.5 mol-%.
the direct arylation. Miura and co-workers had observed a
First, we studied the reactivity of para-substituted aryl
very different behaviour in the presence of a 2-thiophene- bromides (Table 3). In the presence of electron-deficient
carboxamide.[11] With this substrate, the carbamoyl group aryl bromides such as 4-bromoacetophenone, 4-bromo-
acts as a directing group and favours the arylation at C3 of benzaldehyde, methyl 4-bromobenzoate, 4-bromobenzo-
thiophene (Scheme 1, left).
nitrile and 4-trifluoromethylbromobenzene and the catalyst
Next, we examined the influence of several reaction con- (0.5–0.1 mol-%), products 2c and 5–8 were obtained in
ditions. The use of DMF or NMP gave 4 in slightly lower good yields (Table 3, Entries 1–10). On the other hand, in
yields than the reactions performed in DMAc (Table 2, En- the presence of 4-bromonitrobenzene, the formation of sev-
tries 2 and 3). Again, dioxane was found to be ineffective eral unidentified products was formed, and 9 was not iso-
for this reaction (Table 2, Entry 4). In the presence of car- lated (Table 3, Entries 11–13).
bonates and NaOAc or KOH as the base, poor yields of 4
were obtained as a result of low conversions of 3-bromo-
pyridine (Table 2, Entries 7–11). On the other hand, the use
of CsOAc gave 4 in high yield (Table 2, Entry 6). Lower
reaction temperatures led to lower yields of 4 (Table 2, En-
tries 13 and 14). Finally, the addition of phosphane ligands
to the reaction mixture did not improve the yield of this
reaction (Table 2, Entries 16–19).
Then, the scope and limitations for the coupling of N-
(furan-2-ylmethyl)acetamide with the use of other aryl bro-
mides was investigated (Scheme 4, Tables 3–5). As CsOAc
is a relatively expensive base, we selected KOAc instead in
combination with DMAc as the solvent and Pd(OAc)2 (0.5–
0.01 mol-%) as the catalyst at 150 °C as the reaction condi-
tions.
The direct arylation of N-(furan-2-ylmethyl)acetamide
appears to be more difficult than the arylation of 2-n-butyl-
furan. For example, high yields of coupling products were
obtained for the coupling of several electron-deficient aryl
bromides with 2-n-butylfuran by using only 0.01 mol-% of
Pd(OAc)2 as the catalyst.[6f] On the other hand, with N-
(furan-2-ylmethyl)acetamide, low yields were obtained by
using this substrate/catalyst ratio (Table 3, Entries 2
and 4).
As expected, electron-rich aryl bromides were generally
found to be less reactive (Table 3, Entries 17–30). In the
presence of 4-bromotoluene or 1-bromo-4-tert-butylben-
zene, good yields of 59 and 80% were obtained in the pres-
ence of 0.1 mol-% of Pd(OAc)2 as the catalyst. 4-Bromoani-
sole was found to have poor reactivity. Several reaction con-
ditions were employed, but the highest yield of 13 was 31%
(Table 3, Entries 25–29).
Finally, the strongly deactivated aryl bromide 4-bromo-
N,N-dimethylaniline was employed. However, this substrate
was recovered unreacted (Table 3, Entry 30). With 4-bro-
moanisole or 4-bromo-N,N-dimethylaniline, the oxidative
addition to palladium is probably the rate-limiting step of
the reaction. Therefore, with such substrates, palladium as-
sociated to electron-rich monodentate phosphane ligands
should be employed as the catalyst.[2a]
Scheme 4. Coupling of N-(furan-2-ylmethyl)acetamide with aryl
bromides.
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Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
Table 3. Palladium-catalysed coupling of N-(furan-2-ylmethyl)acetamide with para-substituted aryl bromides (Scheme 4).
[a] Conditions: N-(furan-2-ylmethyl)acetamide (2 equiv.), aryl bromide (1 equiv.), base (2 equiv.), DMAc, 150 °C, 16 h, isolated yields.
It should be noted that with 4-bromotoluene, 4-tert- products 11–13. For this ligand-free procedure, under quite
butylbromobenzene or 4-bromoanisole, the use of a higher high palladium concentrations (Ͼ0.5 mol-%), so-called
loading of Pd(OAc)2 (0.5 mol-%) did not give coupling “palladium black” generally forms more rapidly. This “pal-
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J. Roger, H. Doucet
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ladium black” is inactive for such catalysed reactions. Con- of 2-bromoacetophenone, the formation of 20 was not ob-
sequently, the yields of coupling products are often not in- served (Table 4, Entry 8).
creased by a higher catalyst loading.
Next, we explored the reactivity of N-(furan-2-ylmethyl)-
As expected, the reactivity of meta-substituted aryl bro- acetamide (3) with four heteroaryl bromides. The results de-
mides was found to be very similar to the para-substituted picted in Table 5 also reveal the good performance of the
ones (Table 4, Entries 1–7). In the presence of 0.1 mol-% phosphane-free Pd(OAc)2 procedure in the direct coupling
of catalyst, products 15–19 were obtained in 71–90% yield. with 3- or 4-bromopyridines, 4-bromoisoquinoline or 5-bro-
ortho-Substituents on the aryl bromides generally have a mopyrimidine. With these substrates, target products 4 and
more important influence on the yields of palladium-cata- 24–26 were obtained in 80–88% yields.
lysed reactions as a result of their steric and/or coordination
As the deprotection of BOC-substituted amines is gen-
properties.[15] ortho-Substituted 2-bromobenzonitrile, 1- erally easier than the deprotection of amides, we examined
bromo-2-(trifluoromethyl)benzene or 1-bromonaphthalene the coupling of tert-butyl (furan-2-ylmethyl)carbamate (27)
reacted with N-(furan-2-ylmethyl)acetamide by using 0.5– with three aryl bromides (Scheme 5). Carbamates are less
0.1 mol-% of Pd(OAc)2 and gave 21–23 in 62–90% yield thermally stable than amides; therefore, the reactions were
(Table 4, Entries 9–12). On the other hand, in the presence performed at 120 °C instead of 150 °C. Target compounds
Table 4. Palladium-catalysed coupling of N-(furan-2-ylmethyl)acetamide with meta- or ortho-substituted aryl bromides (Scheme 4).
[a] Conditions: N-(furan-2-ylmethyl)acetamide (2 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.), DMAc, 150 °C, 16 h, isolated yields.
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Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
Table 5. Palladium-catalysed coupling of N-(furan-2-ylmethyl)acet- 28–30 were obtained in good yields. Again, the reaction was
amide with heteroaryl bromides (Scheme 4).
found to be highly regioselective, as only the 5-arylation
products were obtained.
Scheme 5. Coupling of tert-butyl (furan-2-ylmethyl)carbamate with
aryl bromides.
Then, we protected furfurylamine using a benzyl substit-
uent. In the presence of this reactant, using 3-bromopyr-
idine as the coupling partner and either Pd(OAc)2 or
PdCl(C3H5)(dppb) as the catalysts. In both cases, a mixture
of several unidentified products was formed, and 32 was
[a] Conditions: Pd(OAc)2, N-(furan-2-ylmethyl)acetamide (2 equiv.),
aryl bromide (1 equiv.), KOAc (2 equiv.), DMAc, 150 °C, 16 h, iso-
lated yields. [b] KOAc (3 equiv.).
Table 6. Palladium-catalysed coupling of N-[2-(thiophen-2-yl)methyl]acetamide with aryl bromides (Scheme 8).
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J. Roger, H. Doucet
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not isolated (Scheme 6). On the other hand, the use of di- than the reactivity of 2-n-butylthiophene. In the presence of
benzyl(furan-2-ylmethyl)amine (33) led regioselectively to 2-n-butylthiophene, the most reactive aryl bromides were
the desired 5-arylated furan compound 34 in 76% yield. successfully coupled by using only 0.01 mol-% of Pd-
However, in terms of atom economy, the use of a BOC pro- (OAc)2 as the catalyst.[5h] On the other hand, the reaction
tecting group for these reactions is probably more suitable. of 4-bromobenzaldehyde or 4-bromopropiophenone with
35 required 0.5–0.1 mol-% of catalyst to obtain 36 and 37
in high yields (Table 6, Entries 1 and 2). The use of electron-
deficient meta- or ortho-substituted aryl bromides also gave
coupling products 39–42 in good yields (Table 6, Entries 6–
9). On the other hand, the reactivity of the electron-rich
aryl bromide 4-tert-butylbromobenzene was found to be
different, and a much higher yield was obtained by using
K2CO3 as the base (Table 6, Entries 4 and 5).
We also studied the reactivity of tert-butyl (thiophen-2-
ylmethyl)carbamate (43; Scheme 8). Both 4-bromobenzal-
Scheme 6. Coupling of benzyl- or dibenzyl(furan-2-ylmethyl)amine
dehyde and 4-bromobenzonitrile gave target 5-arylated
thiophenes 44 and 45. However, as the reactions had to be
performed at a lower temperature of 120 °C, 2 mol-% of the
catalyst had to be employed to obtain good conversions of
these aryl bromides.
with 3-bromopyridine.
Then, the reactivity of N-(thiophen-2-ylmethyl)acet-
amide (35) was examined (Scheme 7, Table 6). We had pre-
viously observed that the reactivity of thiophenes and fu-
rans for palladium-catalysed direct arylation using Pd(OAc)
as the catalyst is quite similar.[5h,6f] As expected, in the pres-
ence of 35, the arylation was completely regioselective at
C5. However, the reactivity of 35 was found to be lower
Scheme 8. Coupling of tert-butyl (thiophen-2-ylmethyl)carbamate
with aryl bromides.
Finally,weexaminedthereactivityofN-[2-(thiophen-2-yl)-
ethyl]acetamide (46; Scheme 9, Table 7). Four aryl bromides
were employed, and in all cases, 5-arylated thiophene deriv-
Scheme 7. Coupling of N-(thiophen-2-ylmethyl)acetamide with
aryl bromides.
Table 7. Palladium-catalysed coupling of N-[2-(thiophen-2-yl)ethyl]acetamide with aryl bromides (Scheme 9).
[a] Conditions: Pd(OAc)2, N-[2-(thiophen-2-yl)ethyl]acetamide (2 equiv.), aryl bromide (1 equiv.), base (2 equiv.), DMAc, 150 °C, 16 h,
isolated yields. [b] PdCl(C3H5)(dppb) (0.01 equiv.) as the catalyst.
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Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
General Procedure for Coupling Reactions: In a typical experiment,
atives 47–50 were obtained in very good yields. In the pres-
ence of the electron-deficient aryl bromides 4-bromobenzal-
dehyde and 2-bromobenzonitrile or in the presence of 3-
bromopyridine, 0.1 mol-% of Pd(OAc)2 with KOAc were
employed as the reaction conditions, whereas in the pres-
ence of 4-bromotoluene the use of 1 mol-% of
PdCl(C3H5)(dppb) with K2CO3 as the base should be pre-
ferred.
the aryl bromide (1 mmol), heteroaryl derivative (2 mmol), base
(see Tables, 2 mmol) and [Pd] (see Tables) were dissolved in DMAc
(5 mL) under an argon atmosphere. The reaction mixture was
stirred at 120 or 150 °C (see Tables) for 16 h. Then, the solvent
was evaporated and the product was purified by silica gel column
chromatography.
N-({5-[4-(Trifluoromethyl)phenyl]furan-2-yl}methyl)acetamide (2c):
The reaction of 1-bromo-4-(trifluoromethyl)benzene (0.225 g,
1 mmol), N-(furan-2-ylmethyl)acetamide (0.278 g, 2 mmol) and
KOAc (0.196 g, 2 mmol) in the presence of Pd(OAc)2 (1.2 mg,
0.005 mmol) afforded 2c in 81% (0.229 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H, Ar), 7.58 (d, J =
8.0 Hz, 2 H, Ar), 6.66 (d, J = 4.0 Hz, 1 H, furan), 6.31 (d, J =
4.0 Hz, 1 H, furan), 6.23 (s, 1 H, NH), 4.46 (d, J = 5.2 Hz, 2 H,
CH2), 2.01 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.0, 152.1, 141.1, 133.6 (q, J = 1.3 Hz), 129.1 (q, J = 32.2 Hz),
125.9 (q, J = 271.6 Hz), 125.6 (q, J = 3.6 Hz), 123.5, 109.9, 107.8,
36.6, 23.1 ppm. C14H12F3NO2 (283.25): calcd. C 59.37, H 4.27;
found C 59.21, H 4.20.
Scheme 9. Coupling of N-[2-(thiophen-2-yl)ethyl]acetamide with
aryl bromides.
N-({3-[4-(Trifluoromethyl)phenyl]furan-2-yl}methyl)acetamide (2d):
1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 2 H, Ar),
7.54 (d, J = 8.0 Hz, 2 H, Ar), 7.43 (d, J = 1.9 Hz, 1 H, furan), 6.55
(d, J = 1.9 Hz, 1 H, furan), 5.83 (s, 1 H, NH), 4.58 (d, J = 5.3 Hz,
2 H, CH2), 2.01 (s, 3 H, CH3) ppm.
Conclusions
In conclusion, these results demonstrate that protected
furfurylamine or 2-(aminoalkyl)thiophene derivatives can
be employed in the palladium-catalysed direct 5-arylation.
These substrates have been protected with a BOC substitu-
ent or as amides. A low loading of a phosphane-free cata-
lyst gave regioselectively the 5-arylated compounds. It
should be noted that the 3-arylation products were not de-
tected, as these methylacetamide or methylcarbamate sub-
stituents on furan or thiophene do not act as directing
groups for the direct arylation reaction. Higher yields were
generally obtained in the presence of electron-deficient aryl
bromides than with electron-rich aryl bromides. However, a
wide range of functions such as acetyl, propionyl, formyl,
ester, nitrile, trifluoromethyl or fluoro on the aryl bromide
is tolerated. The major byproducts of these couplings are
AcOH/KBr instead of metallic salts that are encountered
with more classical coupling procedures. For this reason,
this reaction should give economically viable and environ-
mentally attractive access to 5-arylated furfurylamine or 2-
(aminoalkyl)thiophene derivatives.
N-({5-[4-(Trifluoromethyl)phenyl]furan-2-yl}methyl)formamide (2e):
1H NMR (300 MHz, CDCl3): δ = 8.27 (s, 1 H, CHO), 7.71 (d, J =
8.0 Hz, 2 H, Ar), 7.61 (d, J = 8.0 Hz, 2 H, Ar), 6.69 (d, J = 4.0 Hz,
1 H, furan), 6.36 (d, J = 4.0 Hz, 1 H, furan), 6.10 (s, 1 H, NH),
4.55 (d, J = 5.3 Hz, 2 H, CH2) ppm.
N-({3-[4-(Trifluoromethyl)phenyl]furan-2-yl}methyl)formamide (2f):
1H NMR (300 MHz, CDCl3): δ = 8.24 (s, 1 H, CHO), 7.67 (d, J =
8.0 Hz, 2 H, Ar), 7.54 (d, J = 8.0 Hz, 2 H, Ar), 7.44 (d, J = 1.5 Hz,
1 H, furan), 6.56 (d, J = 1.5 Hz, 1 H, furan), 5.95 (s, 1 H, NH),
4.64 (d, J = 5.3 Hz, 2 H, CH2) ppm.
(Trifluoromethyl)benzene (2g): 1H NMR (300 MHz, CDCl3): δ =
7.75–7.25 (m, 5 H, Ar) ppm. Characterised by GC–MS analysis.
4,4Ј-Bis(trifluoromethyl)biphenyl (2h): 1H NMR (300 MHz,
CDCl3): δ = 7.75–7.67 (m, 8 H, Ar) ppm. Characterised by GC–
MS analysis.
(Furan-2-ylmethyl)[4-(trifluoromethyl)phenyl]amine (2i): 1H NMR
(500 MHz, CDCl3): δ = 7.44 (d, J = 8.0 Hz, 2 H, Ar), 7.40 (dd, J
= 1.8, 0.8 Hz, 1 H, furan), 6.70 (d, J = 8.0 Hz, 2 H, Ar), 6.36 (dd,
J = 3.2, 1.8 Hz, 1 H, furan), 6.27 (d, J = 3.2 Hz, 1 H, furan), 4.35
(d, J = 3.2 Hz, 2 H, CH2) ppm.
N-(Furan-2-ylmethyl)acetamide (3): Acetic anhydride (6.5 mL,
67.5 mmol) was added slowly to a solution of furfurylamine (1;
5 mL, 54.0 mmol) in THF (10 mL), and the mixture was stirred at
room temperature for 20 h. The solvent was removed, and the resi-
due was taken up in CH2Cl2. The solution was washed with satu-
rated aqueous NaHCO3, dried and evaporated to give 3 in 70%
(5.25 g) yield as a yellow liquid, which was used without any further
Experimental Section
General: Furfurylamine, 2-(aminomethyl)thiophene and DMAc
(99%) were purchased from Acros. Pd(OAc)2, [2-(thiophen-2-yl)-
ethyl]amine and KOAc (99%) were purchased from Alfa Aesar.
These compounds were not purified before use.
1
purification. H NMR (300 MHz, CDCl3): δ = 7.49 (s, 1 H, NH),
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 the solution was then 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.
7.18 (m, 1 H, furan), 6.16 (m, 1 H, furan), 6.06 (m, 1 H, furan),
4.21 (d, J = 5.5 Hz, 2 H, CH2), 1.82 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.6, 151.1, 141.5, 109.9, 106.7 ppm.
C7H9NO2 (139.15): calcd. C 60.42, H 6.52; found C 60.60, H 6.47.
General Procedure for Catalysed Reactions: As a typical experi-
ment, the reaction of 3-bromopyridine (0.157 g, 1 mmol), N-(furan-
2-ylmethyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g,
Eur. J. Org. Chem. 2010, 4412–4425
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4419

J. Roger, H. Doucet
FULL PAPER
2 mmol) at 150 °C during 16 h in DMAc (5 mL) in the presence
of Pd(OAc)2 (0.23 mg, 0.001 mmol) under an argon atmosphere
afforded the corresponding product N-{[5-(pyridin-3-yl)furan-2-yl]-
methyl}acetamide (4) after evaporation and filtration through silica
gel (pentane/ether) in 71% (0.154 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.79 (s, 1 H, pyridine), 8.40 (m, 1 H, pyridine), 7.82
(d, J = 4.0 Hz, 1 H, pyridine), 7.24 (m, 1 H, pyridine), 6.70 (s, 1
H, NH), 6.60 (d, J = 4.0 Hz, 1 H, furan), 6.29 (d, J = 4.0 Hz, 1 H,
in the presence of PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol) afforded
10 in 78% (0.182 g) yield. H NMR (300 MHz, CDCl3): δ = 7.58
1
(dd, J = 8.6, 5.5 Hz, 2 H, Ar), 7.06 (t, J = 8.6 Hz, 2 H, Ar), 6.48
(d, J = 4.0 Hz, 1 H, furan), 6.28 (d, J = 4.0 Hz, 1 H, furan), 6.06
(s, 1 H, NH), 4.45 (d, J = 5.2 Hz, 2 H, NH2), 2.00 (s, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9, 162.2 (d, J =
247.1 Hz), 152.7, 150.8, 126.9 (d, J = 3.5 Hz), 125.3 (d, J = 7.0 Hz),
115.6 (d, J = 21.6 Hz), 109.7, 105.4, 36.6, 23.1 ppm. C13H12FNO2
furan), 4.44 (d, J = 5.2 Hz, 2 H, CH2), 2.00 (s, 3 H, CH3) ppm. (233.24): calcd. C 66.94, H 5.19; found C 66.99, H 5.30.
13C NMR (75 MHz, CDCl3): δ = 170.0, 152.2, 150.3, 147.9, 144.9,
130.6, 126.6, 123.5, 109.7, 107.3, 36.5, 23.0 ppm. C12H12N2O2
(216.24): calcd. C 66.65, H 5.59; found C 66.72, H 5.70.
N-{[5-(4-Methylphenyl)furan-2-yl]methyl}acetamide (11): The reac-
tion of 4-bromotoluene (0.171 g, 1 mmol), N-(furan-2-ylmethyl)-
acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
N-{[5-(4-Acetylphenyl)furan-2-yl]methyl}acetamide (5): The reac-
presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 11 in 59%
tion of 4-bromoacetophenone (0.199 g, 1 mmol), N-(furan-2-yl- (0.135 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.51 (d, J =
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) 8.3 Hz, 2 H, Ar), 7.16 (d, J = 8.3 Hz, 2 H, Ar), 6.50 (d, J = 4.0 Hz,
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 5 in
86% (0.221 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J 4.45 (d, J = 5.2 Hz, 2 H, CH2), 2.34 (s, 3 H, CH3), 2.01 (s, 3 H,
= 8.3 Hz, 2 H, Ar), 7.64 (d, J = 8.3 Hz, 2 H, Ar), 6.67 (d, J =
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.7, 153.8, 150.3,
4.0 Hz, 1 H, furan), 6.60 (s, 1 H, NH), 6.31 (d, J = 4.0 Hz, 1 H, 137.2, 129.3, 127.8, 123.6, 109.6, 104.9, 36.7, 23.1, 21.2 ppm.
1 H, furan), 6.28 (d, J = 4.0 Hz, 1 H, furan), 6.02 (s, 1 H, NH),
furan), 4.46 (d, J = 5.2 Hz, 2 H, CH2), 2.54 (s, 3 H, CH3), 2.01 (s,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 198.1, 170.8,
153.1, 152.8, 135.9, 135.2, 129.5, 123.9, 110.5, 109.0, 37.2, 27.1,
23.6 ppm. C15H15NO3 (257.28): calcd. C 70.02, H 5.88; found C
70.04, H 5.98.
C14H15NO2 (229.27): calcd. C 73.34, H 6.59; found C 73.50, H
6.70.
N-{[5-(4-tert-Butylphenyl)furan-2-yl]methyl}acetamide (12): The re-
action of 1-bromo-4-tert-butylbenzene (0.213 g, 1 mmol), N-(furan-
2-ylmethyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g,
2 mmol) in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) af-
N-{[5-(4-Formylphenyl)furan-2-yl]methyl}acetamide (6): The reac-
tion of 4-bromobenzaldehyde (0.185 g, 1 mmol), N-(furan-2-yl-
1
forded 12 in 80% (0.217 g) yield. H NMR (300 MHz, CDCl3): δ
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) = 7.55 (d, J = 8.3 Hz, 2 H, Ar), 7.37 (d, J = 8.3 Hz, 2 H, Ar), 6.49
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 6 in
(d, J = 4.0 Hz, 1 H, furan), 6.26 (d, J = 4.0 Hz, 1 H, furan), 6.20
(s, 1 H, NH), 4.44 (d, J = 5.2 Hz, 2 H, CH2), 1.99 (s, 3 H, CH3),
84% (0.204 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.90 (s, 1
H, CHO), 7.80 (d, J = 8.3 Hz, 2 H, Ar), 7.69 (d, J = 8.3 Hz, 2 H, 1.31 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8,
Ar), 6.72 (d, J = 4.0 Hz, 1 H, furan), 6.60 (s, 1 H, NH), 6.33 (d, J
= 4.0 Hz, 1 H, furan), 4.45 (d, J = 5.2 Hz, 2 H, CH2), 2.03 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.5, 170.1, 152.8,
151.9, 135.7, 134.6, 130.2, 123.5, 110.0, 109.0, 36.5, 23.0 ppm.
C14H13NO3 (243.26): calcd. C 69.12, H 5.39; found C 69.20, H
5.34.
153.7, 150.4, 142.0, 127.8, 125.5, 123.4, 109.5, 105.1, 36.7, 34.5,
31.1, 23.1 ppm. C17H21NO2 (271.35): calcd. C 75.25, H 7.80; found
C 75.41, H 7.99.
N-{[5-(4-Methoxyphenyl)furan-2-yl]methyl}acetamide (13): The re-
action of 4-bromoanisole (0.187 g, 1 mmol), N-(furan-2-ylmethyl)-
acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
presence of PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol) afforded 13 in
30% (0.074 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.54 (d, J
= 8.3 Hz, 2 H, Ar), 6.90 (d, J = 8.3 Hz, 2 H, Ar), 6.41 (d, J =
4.0 Hz, 1 H, furan), 6.26 (d, J = 4.0 Hz, 1 H, furan), 6.20 (s, 1 H,
Methyl 4-{5-[(Acetylamino)methyl]-furan-2-yl}benzoate (7): The re-
action of methyl 4-bromobenzoate (0.215 g, 1 mmol), N-(furan-2-
ylmethyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) afforded 7 in
84% (0.230 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J NH), 4.44 (d, J = 5.2 Hz, 2 H, CH2), 3.81 (s, 3 H, CH3), 2.00 (s, 3
= 8.3 Hz, 2 H, Ar), 7.65 (d, J = 8.3 Hz, 2 H, Ar), 6.69 (d, J =
4.0 Hz, 1 H, furan), 6.33 (d, J = 4.0 Hz, 1 H, furan), 6.05 (s, 1 H,
NH), 4.48 (d, J = 5.2 Hz, 2 H, CH2), 3.90 (s, 3 H, CH3), 2.02 (s, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9, 166.7,
152.5, 152.1, 134.4, 130.0, 128.5, 123.3, 110.0, 108.1, 52.1, 36.7,
23.2 ppm. C15H15NO4 (273.28): calcd. C 65.92, H 5.53; found C
65.80, H 5.61.
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8, 159.0,
153.6, 150.1, 125.0, 123.6, 114.0, 109.5, 104.1, 55.2, 36.7, 23.0 ppm.
C14H15NO3 (245.27): calcd. C 68.56, H 6.16; found C 68.40, H
6.25.
N-{[5-(3-Acetylphenyl)furan-2-yl]methyl}acetamide (15): The reac-
tion of 3-bromoacetophenone (0.199 g, 1 mmol), N-(furan-2-yl-
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 15 in
82% (0.211 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1
N-{[5-(4-Cyanophenyl)furan-2-yl]methyl}acetamide (8): The reac-
tion of 4-bromobenzonitrile (0.182 g, 1 mmol), N-(furan-2-ylmeth-
yl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the H, Ar), 7.75–7.65 (m, 2 H, Ar), 7.37 (t, J = 7.3 Hz, 1 H, Ar), 6.70
presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 8 in 90%
(s, 1 H, NH), 6.56 (d, J = 4.0 Hz, 1 H, furan), 6.25 (d, J = 4.0 Hz,
1 H, furan), 4.41 (d, J = 5.2 Hz, 2 H, CH2), 2.54 (s, 3 H, CH3),
(0.216 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J =
8.3 Hz, 2 H, Ar), 7.56 (d, J = 8.3 Hz, 2 H, Ar), 6.71 (d, J = 4.0 Hz, 1.99 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 198.9,
1 H, furan), 6.60 (s, 1 H, NH), 6.33 (d, J = 4.0 Hz, 1 H, furan), 170.1, 152.2, 151.6, 137.2, 130.9, 128.8, 127.8, 127.0, 122.8, 109.6,
4.45 (d, J = 5.2 Hz, 2 H, CH2), 2.01 (s, 3 H, CH3) ppm. 13C NMR 106.7, 36.5, 26.5, 22.9 ppm. C15H15NO3 (257.28): calcd. C 70.02,
(75 MHz, CDCl3): δ = 170.7, 153.6, 151.9, 134.9, 133.0, 124.2, H 5.88; found C 70.11, H 5.70.
119.5, 110.6, 109.8, 109.7, 36.5, 23.6 ppm. C14H12N2O2 (240.26):
calcd. C 69.99, H 5.03; found C 70.05, H 5.17.
N-{[5-(3-Formylphenyl)furan-2-yl]methyl}acetamide (16): The reac-
tion of 3-bromobenzaldehyde (0.185 g, 1 mmol), N-(furan-2-yl-
N-{[5-(4-Fluorophenyl)furan-2-yl]methyl}acetamide (10): The reac-
tion of 4-bromofluorobenzene (0.175 g, 1 mmol), N-(furan-2-yl-
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 16 in
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) 74% (0.180 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.95 (s, 1
4420
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4412–4425

Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
H, CHO), 8.82 (s, 1 H, Ar), 7.77 (d, J = 8.3 Hz, 1 H, Ar), 7.68 (d,
J = 8.3 Hz, 1 H, Ar), 7.46 (t, J = 7.8 Hz, 1 H, Ar), 6.60 (m, 2 H,
NH and furan), 6.29 (d, J = 4.0 Hz, 1 H, furan), 4.44 (d, J =
8.3 Hz, 1 H, Ar), 7.52 (t, J = 7.7 Hz, 1 H, Ar), 7.36 (t, J = 7.7 Hz,
1 H, Ar), 6.11 (d, J = 4.0 Hz, 1 H, furan), 6.45 (m, 1 H, NH), 6.28
(d, J = 4.0 Hz, 1 H, furan), 4.44 (d, J = 5.2 Hz, 2 H, CH2), 1.96
5.2 Hz, 2 H, CH2), 2.00 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1, 151.9,
CDCl3): δ = 192.0, 170.2, 151.9, 151.8, 136.5, 131.4, 129.3, 129.1,
149.9, 131.6, 129.6, 129.3, 127.6, 126.5 (q, J = 5.0 Hz), 126.4 (q, J
128.5, 124.0, 109.7, 107.1, 36.5, 23.0 ppm. C14H13NO3 (243.26): = 30.9 Hz), 124.0 (q, J = 273.3 Hz), 110.7, 109.2, 36.5, 22.8 ppm.
calcd. C 69.12, H 5.39; found C 69.01, H 5.30.
C14H12F3NO2 (283.25): calcd. C 59.37, H 4.27; found C 59.21, H
4.48.
N-{[5-(3-Cyanophenyl)furan-2-yl]methyl}acetamide (17): The reac-
tion of 3-bromobenzonitrile (0.182 g, 1 mmol), N-(furan-2-yl-
N-{[5-(Naphthalen-1-yl)furan-2-yl]methyl}acetamide (23): The reac-
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) tion of 1-bromonaphthalene (0.207 g, 1 mmol), N-(furan-2-ylmeth-
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 17 in
90% (0.216 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.80–7.70
(m, 2 H, Ar), 7.45–7.35 (m, 2 H, Ar), 6.87 (s, 1 H, NH), 6.60 (d, J
= 4.0 Hz, 1 H, furan), 6.28 (d, J = 4.0 Hz, 1 H, furan), 4.42 (d, J
yl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 23 in 79%
(0.209 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.40 (d, J =
8.0 Hz, 1 H, Ar), 7.95–7.80 (m, 2 H, Ar), 7.71 (d, J = 8.0 Hz, 1 H,
= 5.2 Hz, 2 H, CH2), 2.00 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, Ar), 7.60–7.40 (m, 3 H, Ar), 6.70 (m, 1 H, NH), 6.63 (d, J = 4.0 Hz,
CDCl3): δ = 170.8, 152.9, 151.3, 132.1, 130.7, 130.0, 127.9, 127.2,
119.1, 113.1, 110.2, 108.2, 37.0, 23.5 ppm. C14H12N2O2 (240.26):
calcd. C 69.99, H 5.03; found C 70.14, H 5.20.
1 H, furan), 6.37 (d, J = 4.0 Hz, 1 H, furan), 4.50 (d, J = 5.2 Hz,
2 H, CH2), 1.97 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 170.0, 152.6, 151.2, 133.7, 130.0, 128.3, 128.2, 128.1, 126.4,
125.8, 125.7, 125.2, 125.1, 109.9, 109.0, 36.6, 22.8 ppm. C17H15NO2
(265.31): calcd. C 76.96, H 5.70; found C 76.80, H 5.61.
N-({5-[3-(trifluoromethyl)phenyl]furan-2-yl}methyl)acetamide (18):
The reaction of 1-bromo-3-(trifluoromethyl)benzene (0.225 g,
1 mmol), N-(furan-2-ylmethyl)acetamide (0.278 g, 2 mmol) and
KOAc (0.196 g, 2 mmol) in the presence of Pd(OAc)2 (0.23 mg,
0.001 mmol) afforded 18 in 71% (0.201 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.84 (s, 1 H, Ar), 7.80–7.70 (m, 1 H, Ar),
N-{[5-(Pyridin-4-yl)furan-2-yl]methyl}acetamide (24): The reaction
of 4-bromopyridine hydrochloride (0.194 g, 1 mmol), N-(furan-2-yl-
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.294 g, 3 mmol)
in the presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) afforded 24 in
7.50–7.40 (m, 2 H, Ar), 6.63 (d, J = 4.0 Hz, 1 H, furan), 6.31 (d, J 86% (0.186 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.57 (d, J
= 4.0 Hz, 1 H, furan), 6.25 (s, 1 H, NH), 4.45 (d, J = 5.2 Hz, 2 H,
= 6.0 Hz, 2 H, pyridine), 7.46 (d, J = 6.0 Hz, 2 H, pyridine), 6.80
CH2), 2.00 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = (d, J = 4.0 Hz, 1 H, furan), 6.37 (d, J = 4.0 Hz, 1 H, furan), 6.00
169.9, 151.9, 151.8, 131.2, 131.1 (q, J = 31.4 Hz), 129.1, 125.7,
124.2 (q, J = 272.4 Hz), 123.6 (q, J = 3.8 Hz), 120.2 (q, J = 3.8 Hz),
109.7, 107.1, 36.6, 23.0 ppm. C14H12F3NO2 (283.25): calcd. C
59.37, H 4.27; found C 59.45, H 4.40.
(m, 1 H, NH), 4.49 (d, J = 5.2 Hz, 2 H, CH2), 2.04 (s, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8, 153.1, 150.8, 149.9,
137.2, 117.6, 110.0, 109.7, 36.6, 23.2 ppm. C12H12N2O2 (216.24):
calcd. C 66.65, H 5.59; found C 66.50, H 5.74.
N-{[5-(Naphthalen-2-yl)furan-2-yl]methyl}acetamide (19): The reac-
N-{[5-(Pyrimidin-5-yl)furan-2-yl]methyl}acetamide (25): The reac-
tion of 2-bromonaphthalene (0.207 g, 1 mmol), N-(furan-2-ylmeth- tion of 5-bromopyrimidine (0.159 g, 1 mmol), N-(furan-2-ylmeth-
yl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the yl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 19 in 87%
presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) afforded 25 in 88%
(0.231 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1 H, Ar), (0.191 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.00 (s, 1 H,
7.85–7.75 (m, 3 H, Ar), 7.69 (d, J = 8.0 Hz, 1 H, Ar), 7.50–7.40 pyrimidine), 8.88 (s, 2 H, pyrimidine), 6.72 (m, 1 H, NH), 6.71 (d,
(m, 2 H, Ar), 6.63 (d, J = 4.0 Hz, 1 H, furan), 6.40 (s, 1 H, NH),
6.31 (d, J = 4.0 Hz, 1 H, furan), 4.48 (d, J = 5.2 Hz, 2 H, CH2),
J = 4.0 Hz, 1 H, furan), 6.35 (d, J = 4.0 Hz, 1 H, furan), 4.47 (d,
J = 5.2 Hz, 2 H, CH2), 2.01 (s, 3 H, CH3) ppm. 13C NMR
2.00 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0, (75 MHz, CDCl3): δ = 170.0, 156.6, 153.3, 151.3, 147.0, 124.7,
153.5, 151.1, 133.3, 132.5, 128.3, 128.0, 127.8, 127.6, 126.4, 125.8,
109.8, 108.8, 36.4, 22.9 ppm. C11H11N3O2 (217.22): calcd. C 60.82,
122.0, 121.8, 109.7, 106.3, 36.6, 22.9 ppm. C17H15NO2 (265.31): H 5.10; found C 60.70, H 5.22.
calcd. C 76.96, H 5.70; found C 76.87, H 5.55.
N-{[5-(Isoquinolin-4-yl)furan-2-yl]methyl}acetamide (26): The reac-
N-{[5-(2-Cyanophenyl)furan-2-yl]methyl}acetamide (21): The reac-
tion of 2-bromobenzonitrile (0.182 g, 1 mmol), N-(furan-2-yl-
tion of 4-bromoisoquinoline (0.208 g, 1 mmol), N-(furan-2-ylmeth-
yl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
methyl)acetamide (0.278 g, 2 mmol) and KOAc (0.196 g, 2 mmol) presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) afforded 26 in 87%
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 21 in
(0.232 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.11 (s, 1 H,
90% (0.216 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.79 (d, J isoquinoline), 8.64 (s, 1 H, isoquinoline), 8.30 (d, J = 8.0 Hz, 1 H,
= 8.3 Hz, 1 H, Ar), 7.66 (d, J = 8.3 Hz, 1 H, Ar), 7.58 (t, J =
7.7 Hz, 1 H, Ar), 7.30 (t, J = 7.7 Hz, 1 H, Ar), 7.11 (d, J = 4.0 Hz,
isoquinoline), 7.94 (d, J = 8.0 Hz, 1 H, isoquinoline), 7.71 (t, J =
7.7 Hz, 1 H, isoquinoline), 7.59 (t, J = 7.7 Hz, 1 H, isoquinoline),
1 H, furan), 6.40 (s, 1 H, NH), 6.37 (d, J = 4.0 Hz, 1 H, furan), 6.67 (d, J = 4.0 Hz, 1 H, furan), 6.60 (m, 1 H, NH), 6.41 (d, J =
4.49 (d, J = 5.2 Hz, 2 H, CH2), 2.03 (s, 3 H, CH3) ppm. 13C NMR 4.0 Hz, 1 H, furan), 4.54 (d, J = 5.2 Hz, 2 H, CH2), 2.02 (s, 3 H,
(75 MHz, CDCl3): δ = 170.1, 152.4, 149.2, 134.0, 132.9, 132.8, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0, 152.3, 152.0,
127.1, 125.7, 119.0, 111.0, 109.7, 106.6, 36.5, 23.0 ppm.
C14H12N2O2 (240.26): calcd. C 69.99, H 5.03; found C 70.18, H
4.87.
150.2, 141.6, 132.3, 131.1, 128.3, 128.1, 127.4, 124.4, 122.0, 110.9,
109.5, 36.7, 23.1 ppm. C16H14N2O2 (266.29): calcd. C 72.16, H
5.30; found C 72.20, H 5.07.
N-({5-[2-(Trifluoromethyl)phenyl]furan-2-yl}methyl)acetamide (22): tert-Butyl (Furan-2-ylmethyl)carbamate (27): Furfurylamine (1;
The reaction of 1-bromo-2-(trifluoromethyl)benzene (0.225 g,
1 mmol), N-(furan-2-ylmethyl)acetamide (0.278 g, 2 mmol) and
KOAc (0.196 g, 2 mmol) in the presence of Pd(OAc)2 (1.2 mg,
0.005 mmol) afforded 22 in 62% (0.176 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 1 H, Ar), 7.66 (d, J =
2.0 mL, 21.6 mmol) was slowly added to a solution of di-tert-butyl
dicarbonate (5.3 mg, 23.8 mmol) and triethylamine (3 mL,
21.6 mmol) in CH2Cl2 (5 mL), and the mixture was stirred at room
temperature for 20 h. The solvent was removed, and the residue
was taken up in CH2Cl2. The solution was washed with saturated
Eur. J. Org. Chem. 2010, 4412–4425
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4421

J. Roger, H. Doucet
FULL PAPER
aqueous NaHCO3, dried and evaporated to give 27 in 67% (2.85 g)
yield as a yellow liquid, which was used without any further purifi-
cation. 1H NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 4.0 Hz, 1 H,
furan), 6.29 (t, J = 4.0 Hz, 1 H, furan), 6.19 (d, J = 4.0 Hz, 1 H,
furan), 4.96 (m, 1 H, NH), 4.28 (d, J = 5.5 Hz, 2 H, CH2), 1.44 (s,
(20 mL), and the mixture was stirred at room temperature for 20 h.
The solvent was removed, and the residue was taken up in CH2Cl2.
Then, the solution was washed with saturated aqueous NaHCO3,
dried, evaporated and purified by flash column chromatography.
Elution with pentane/ether (90:10) gave 33 in 66% (3.95 g) yield as
9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.2, 152.6, a yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 7.68–7.44 (m, 11
142.6, 110.0, 107.5, 80.2, 38.3, 28.0 ppm. C10H15NO3 (197.23): H, Ar and furan), 6.54 (m, 1 H, furan), 6.42 (m, 1 H, furan), 3.88
calcd. C 60.90, H 7.67; found C 60.85, H 7.60.
(s, 6 H, 3 CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.6, 141.8,
139.3, 128.7, 128.1, 126.8, 109.9, 108.5, 57.4, 49.0 ppm. C19H19NO
(277.36): calcd. C 82.28, H 6.90; found C 82.14, H 6.77.
tert-Butyl {[5-(4-Formylphenyl)furan-2-yl]methyl}carbamate (28):
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol), tert-butyl
(furan-2-ylmethyl)carbamate (0.394 g, 2 mmol) and KOAc (0.196 g,
2 mmol) in the presence of PdCl(C3H5)(dppb) (12.2 mg,
Dibenzyl{[5-(pyridin-3-yl)furan-2-yl]methyl}amine (34): The reac-
tion of 3-bromopyridine (0.157 g, 1 mmol), dibenzyl(furan-2-yl-
0.02 mmol) at 120 °C afforded 28 in 77% (0.232 g) yield. 1H NMR methyl)amine (0.554 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the
(300 MHz, CDCl3): δ = 9.92 (s, 1 H, CHO), 7.82 (d, J = 8.4 Hz, 2
H, Ar), 7.71 (d, J = 8.4 Hz, 2 H, Ar), 6.72 (d, J = 3.3 Hz, 1 H,
presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) afforded 34 in
76% (0.269 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.01 (s, 1 H,
furan), 6.32 (d, J = 3.3 Hz, 1 H, furan), 5.21 (m, 1 H, NH), 4.35 pyridine), 8.53 (d, J = 4.3 Hz, 1 H, pyridine), 7.94 (d, J = 7.8 Hz, 1
(d, J = 5.7 Hz, 2 H, CH2), 1.46 (s, 9 H, tBu) ppm. 13C NMR
H, pyridine), 7.55–7.28 (m, 11 H, Ar and pyridine), 6.73 (d, J =
(75 MHz, CDCl3): δ = 191.4, 155.5, 153.5, 151.8, 135.8, 134.6, 3.1 Hz, 1 H, furan), 6.34 (d, J = 3.1 Hz, 1 H, furan), 3.78–3.70 (m,
130.1, 123.4, 109.4, 108.9, 79.7, 37.7, 28.2 ppm. C17H19NO4
(301.34): calcd. C 67.76, H 6.36; found C 67.88, H 6.45.
6 H, 3 CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.5, 150.1,
147.8, 145.1, 139.2, 130.3, 128.6, 128.2, 126.9, 123.4, 110.7, 107.0,
57.6, 48.9 ppm. C24H22N2O (354.44): calcd. C 81.33, H 6.26; found
C 81.41, H 6.37.
tert-Butyl
({5-[4-(Trifluoromethyl)phenyl]furan-2-yl}methyl)carb-
amate (29): The reaction of 1-bromo-4-(trifluoromethyl)benzene
(0.225 g, 1 mmol), tert-butyl (furan-2-ylmethyl)carbamate (0.394 g, N-(Thiophen-2-ylmethyl)acetamide (35): Acetic anhydride (1.8 mL,
2 mmol) and KOAc (0.196 g, 2 mmol) in the presence of 18.9 mmol) was slowly added to a solution of (thiophen-2-ylmeth-
PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol) at 120 °C afforded 29 in yl)amine (2 mL, 15.8 mmol) in THF (10 mL), and the mixture was
79% (0.270 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.71 (d, J stirred at room temperature for 20 h. Then, the solvent was re-
= 8.4 Hz, 2 H, Ar), 7.61 (d, J = 8.4 Hz, 2 H, Ar), 6.69 (d, J =
3.3 Hz, 1 H, furan), 6.33 (d, J = 3.3 Hz, 1 H, furan), 5.03 (m, 1 H,
NH), 4.38 (d, J = 5.7 Hz, 2 H, CH2), 1.40 (s, 9 H, tBu) ppm. 13C
moved, and the residue was taken up in CH2Cl2. The solution was
washed with saturated aqueous NaHCO3, dried and evaporated to
give 35 in 73% (1.79 g) yield as a yellow solid, which was used
NMR (75 MHz, CDCl3): δ = 155.6, 152.9, 151.8, 133.7, 128.8 (q, without any further purification. 1H NMR (300 MHz, CDCl3): δ
J = 32.2 Hz), 125.6 (q, J = 3.7 Hz), 123.8 (q, J = 272.0 Hz), 123.5, = 7.17 (m, 1 H, thiophene), 7.20–6.90 (m, 3 H, thiophene and NH),
109.2, 107.7, 79.8, 37.8, 28.3 ppm. C17H18F3NO3 (341.32): calcd. C
59.82, H 5.32; found C 59.74, H 5.31.
4.50 (d, J = 5.7 Hz, 2 H, CH2), 1.83 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.0, 141.0, 126.6, 125.6, 124.8, 38.0,
22.7 ppm. C7H9NOS (155.22): calcd. C 54.17, H 5.84; found C
54.30, H 5.99.
tert-Butyl {[5-(Pyridin-3-yl)furan-2-yl]methyl}carbamate (30): The
reaction of 3-bromopyridine (0.157 g, 1 mmol), tert-butyl (furan-2-
ylmethyl)carbamate (0.394 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) at
120 °C afforded 30 in 75% (0.206 g) yield. 1H NMR (300 MHz,
CDCl3): δ = 8.89 (s, 1 H, pyridine), 8.48 (m, 1 H, pyridine), 7.90
(d, J = 7.9 Hz, 1 H, pyridine), 7.30 (m, 1 H, pyridine), 6.68 (d, J
N-{[5-(4-Formylphenyl)thiophen-2-yl]methyl}acetamide (36): The re-
action of 4-bromobenzaldehyde (0.185 g, 1 mmol), N-(thiophen-2-
ylmethyl)acetamide (0.310 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 36 in
87% (0.225 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.96 (s, 1
= 4.0 Hz, 1 H, furan), 6.33 (d, J = 4.0 Hz, 1 H, furan), 5.07 (m, 1 H, CHO), 7.83 (d, J = 8.4 Hz, 2 H, Ar), 7.67 (d, J = 8.4 Hz, 2 H,
H, NH), 4.37 (d, J = 5.7 Hz, 2 H, CH2), 1.47 (s, 9 H, tBu) ppm. Ar), 7.28 (d, J = 3.7 Hz, 1 H, thiophene), 6.96 (d, J = 3.7 Hz, 1 H,
13C NMR (75 MHz, CDCl3): δ = 155.5, 152.9, 149.9, 147.0, 144.2, thiophene), 6.32 (m, 1 H, NH), 4.59 (d, J = 5.8 Hz, 2 H, CH2),
131.2, 127.0, 123.7, 109.1, 107.5, 79.8, 37.7, 28.3 ppm. C15H18N2O3
(274.32): calcd. C 65.68, H 6.61; found C 65.54, H 6.78.
2.05 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.4,
170.0, 143.0, 142.2, 139.8, 124.9, 130.4, 127.8, 125.6, 124.7, 38.5,
23.1 ppm. C14H13NO2S (259.32): calcd. C 64.84, H 5.05; found C
64.69, H 5.12.
Benzyl(furan-2-ylmethyl)amine (31): Benzyl chloride (2.5 mL,
21.7 mmol) was slowly added to a solution of furfurylamine (1;
2 mL, 21.6 mmol) and triethylamine (3 mL, 21.6 mmol) in THF
(10 mL), and the mixture was stirred at room temperature for 20 h.
The solvent was removed, and the residue was taken up in CH2Cl2.
Then, the solution was washed with saturated aqueous NaHCO3,
dried, evaporated and purified by flash column chromatography.
Elution with pentane/ether (90:10) gave 31 in 69% (2.79 g) yield as
N-{[5-(4-Propionylphenyl)thiophen-2-yl]methyl}acetamide (37): The
reaction of 4-bromopropiophenone (0.213 g, 1 mmol), N-(thio-
phen-2-ylmethyl)acetamide (0.310 g, 2 mmol) and KOAc (0.196 g,
2 mmol) in the presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) af-
1
forded 37 in 84% (0.241 g) yield. H NMR (300 MHz, CDCl3): δ
= 7.93 (d, J = 8.4 Hz, 2 H, Ar), 7.60 (d, J = 8.4 Hz, 2 H, Ar), 7.24
(d, J = 3.7 Hz, 1 H, thiophene), 6.94 (d, J = 3.7 Hz, 1 H, thio-
phene), 6.07 (m, 1 H, NH), 4.59 (d, J = 5.8 Hz, 2 H, CH2), 2.99
(q, J = 7.5 Hz, 2 H, CH2), 2.05 (s, 3 H, CH3), 1.23 (t, J = 7.5 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.0, 169.8,
142.6, 142.3, 138.3, 135.5, 128.7, 127.2, 125.3, 124.2, 38.6, 31.7,
23.2, 8.2 ppm. C16H17NO2S (287.38): calcd. C 66.87, H 5.96; found
C 66.97, H 5.84.
1
a yellow liquid. H NMR (300 MHz, CDCl3): δ = 7.45–7.30 (m, 6
H, Ar and furan), 6.37 (m, 1 H, furan), 6.23 (m, 1 H, furan), 3.81
(m, 4 H, 2 CH2), 1.82 (s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.5, 141.1, 139.5, 127.8, 127.6, 126.4, 109.6, 106.3,
52.1, 44.7 ppm. C12H13NO (187.24): calcd. C 76.98, H 7.00; found
C 76.80, H 7.12.
Dibenzyl(furan-2-ylmethyl)amine (33): Benzyl chloride (5 mL,
43.4 mmol) was slowly added to a solution of furfurylamine (1;
N-{[5-(4-tert-Butylphenyl)thiophen-2-yl]methyl}acetamide (38): The
2 mL, 21.6 mmol) and triethylamine (6 mL, 43.2 mmol) in THF reaction of 1-bromo-4-tert-butylbenzene (0.213 g, 1 mmol), N-
4422
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4412–4425

Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
(thiophen-2-ylmethyl)acetamide (0.310 g, 2 mmol) and K2CO3
(1.2 mL, 8.7 mmol) in CH2Cl2 (5 mL), and the mixture was stirred
(0.276 g, 2 mmol) in the presence of Pd(OAc)2 (1.2 mg, at room temperature for 20 h. The solvent was removed, and the
0.005 mmol) afforded 38 in 85% (0.244 g) yield. 1H NMR residue was taken up in CH2Cl2. The solution was washed with
(300 MHz, CDCl3): δ = 7.49 (d, J = 8.0 Hz, 2 H, Ar), 7.38 (d, J =
8.0 Hz, 2 H, Ar), 7.09 (d, J = 4.0 Hz, 1 H, thiophene), 6.90 (d, J
= 4.0 Hz, 1 H, thiophene), 5.88 (m, 1 H, NH), 4.58 (d, J = 5.8 Hz,
saturated aqueous NaHCO3, dried and evaporated to give 43 in
65% yield (1.20 g), which was used without any further purification
as a yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 7.22–7.20 (m,
2 H, CH2), 2.02 (s, 3 H, CH3), 1.33 (s, 9 H, tBu) ppm. 13C NMR 1 H, thiophene), 6.95–6.90 (m, 2 H, thiophene), 4.90 (m, 1 H, NH),
(75 MHz, CDCl3): δ = 169.7, 150.7, 144.4, 139.7, 131.4, 127.0, 4.47 (d, J = 5.5 Hz, 2 H, CH2), 1.46 (s, 9 H, tBu) ppm. 13C NMR
125.8, 125.4, 122.3, 38.7, 34.6, 31.2, 23.3 ppm. C17H21NOS
(287.42): calcd. C 71.04, H 7.36; found C 71.12, H 7.21.
(75 MHz, CDCl3): δ = 155.5, 141.9, 126.7, 125.3, 124.8, 79.6, 39.5,
28.3 ppm. C10H15NO2S (213.30): calcd. C 56.31, H 7.09; found C
56.40, H 7.11.
N-({5-[3,5-Bis(trifluoromethyl)phenyl]thiophen-2-yl}methyl)acet-
amide (39): The reaction of 1-bromo-3,5-bis(trifluoromethyl)-
benzene (0.293 g, 1 mmol), N-(thiophen-2-ylmethyl)acetamide
(0.310 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the presence of Pd-
(OAc)2 (0.23 mg, 0.001 mmol) afforded 39 in 83% (0.305 g) yield.
1H NMR (300 MHz, CDCl3): δ = 7.95 (s, 2 H, Ar), 7.76 (s, 1 H,
Ar), 7.28 (d, J = 4.0 Hz, 1 H, thiophene), 7.00 (d, J = 4.0 Hz, 1 H,
thiophene), 6.05 (m, 1 H, NH), 4.65 (d, J = 5.8 Hz, 2 H, CH2),
2.07 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9,
143.3, 140.4, 136.2, 132.7 (q, J = 32.0 Hz), 127.2, 125.3 (m), 124.8,
123.1 (q, J = 272.8 Hz), 120.6 (m), 38.5, 23.1 ppm. C15H11F6NOS
(367.31): calcd. C 49.05, H 3.02; found C 49.11, H 3.17.
tert-Butyl {[5-(4-Formylphenyl)thiophen-2-yl]methyl}carbamate (44):
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol), tert-butyl
(thiophen-2-ylmethyl)carbamate (0.426 g, 2 mmol), and KOAc
(0.196 g, 2 mmol) in the presence of PdCl(C3H5)(dppb) (12.2 mg,
0.02 mmol) at 120 °C afforded 44 in 74% (0.235 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 9.96 (s, 1 H, CHO), 7.84 (d, J = 8.4 Hz, 2
H, Ar), 7.68 (d, J = 8.4 Hz, 2 H, Ar), 7.27 (d, J = 3.6 Hz, 1 H,
thiophene), 6.95 (d, J = 3.6 Hz, 1 H, thiophene), 5.15 (m, 1 H,
NH), 4.47 (d, J = 5.7 Hz, 2 H, CH2), 1.49 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 191.4, 155.6, 144.2, 141.9, 140.1,
135.0, 130.4, 126.7, 125.7, 124.8, 79.9, 39.8, 28.4 ppm. C17H19NO3S
(317.40): calcd. C 64.33, H 6.03; found C 64.40, H 6.10.
N-{[5-(2-Cyanophenyl)thiophen-2-yl]methyl}acetamide (40): The re-
action of 2-bromobenzonitrile (0.182 g, 1 mmol), N-(thiophen-2-yl-
methyl)acetamide (0.310 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 40 in
87% (0.223 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J
= 8.4 Hz, 1 H, Ar), 7.60–7.50 (m, 2 H, Ar), 7.41 (d, J = 3.7 Hz, 1
H, thiophene), 7.32 (t, J = 7.6 Hz, 1 H, Ar), 6.96 (d, J = 3.7 Hz, 1
H, thiophene), 6.50 (m, 1 H, NH), 4.56 (d, J = 5.8 Hz, 2 H, CH2),
1.99 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1,
143.4, 138.7, 137.2, 134.1, 132.9, 129.3, 127.4, 127.2, 126.8, 118.7,
109.5, 38.2, 22.9 ppm. C14H12N2OS (256.32): calcd. C 65.60, H
4.72; found C 65.70, H 4.83.
tert-Butyl {[5-(4-Cyanophenyl)thiophen-2-yl]methyl}carbamate (45):
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), tert-butyl
(thiophen-2-ylmethyl)carbamate (0.426 g, 2 mmol), and KOAc
(0.196 g, 2 mmol) in the presence of PdCl(C3H5)(dppb) (12.2 mg,
0.02 mmol) at 120 °C afforded 45 in 58% (0.182 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.66–7.62 (m, 4 H, Ar), 7.27 (d, J = 3.6 Hz,
1 H, thiophene), 6.96 (d, J = 3.6 Hz, 1 H, thiophene), 5.02 (m, 1
H, NH), 4.49 (d, J = 5.7 Hz, 2 H, CH2), 1.49 (s, 9 H, tBu) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.5, 144.3, 141.3, 138.6, 132.6,
126.6, 125.7, 124.7, 118.8, 110.4, 80.0, 39.7, 28.3 ppm.
C17H18N2O2S (314.40): calcd. C 64.94, H 5.77; found C 64.88, H
5.80.
N-{[5-(2-Formylphenyl)thiophen-2-yl]methyl}acetamide (41): The re-
action of 2-bromobenzaldehyde (0.185 g, 1 mmol), N-(thiophen-2-
ylmethyl)acetamide (0.310 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 41 in
N-[2-(Thiophen-2-yl)ethyl]acetamide (46): Acetic anhydride
(0.9 mL, 9.4 mmol) was slowly added to a solution of [2-(thiophen-
2-yl)ethyl]amine (1 g, 7.9 mmol) in THF (5 mL), and the mixture
was stirred at room temperature for 20 h. Then, the solvent was
removed, and the residue was taken up in CH2Cl2. The solution
was washed with saturated aqueous NaHCO3, dried and evapo-
rated to give 46 in 72% (0.96 g) yield as a yellow solid, which was
used without any further purification. 1H NMR (300 MHz,
CDCl3): δ = 7.07 (d, J = 5.1 Hz, 1 H, thiophene), 6.87 (dd, J =
5.1, 2.9 Hz, 1 H, thiophene), 6.77 (d, J = 2.9 Hz, 1 H, thiophene),
6.74 (m, 1 H, NH), 3.44 (q, J = 7.0 Hz, 2 H, CH2), 2.97 (t, J =
7.0 Hz, 2 H, CH2), 1.09 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.3, 141.0, 126.6, 124.8, 123.4, 40.7, 29.4, 22.7 ppm.
C8H11NOS (169.25): calcd. C 56.77, H 6.55; found C 56.72, H 6.47.
1
71% (0.184 g) yield. H NMR (300 MHz, CDCl3): δ = 10.16 (s, 1
H, CHO), 7.97 (d, J = 8.4 Hz, 1 H, Ar), 7.60–7.40 (m, 3 H, Ar),
6.97 (d, J = 3.7 Hz, 1 H, thiophene), 6.88 (d, J = 3.7 Hz, 1 H,
thiophene), 6.10 (m, 1 H, NH), 4.62 (d, J = 5.8 Hz, 2 H, CH2),
2.00 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.9,
169.9, 143.4, 138.5, 137.8, 134.0, 133.6, 131.1, 129.3, 128.2, 127.9,
126.5, 38.5, 23.2 ppm. C14H13NO2S (259.32): calcd. C 64.84, H
5.05; found C 64.71, H 4.87.
N-{[5-(2,4-Difluorophenyl)thiophen-2-yl]methyl}acetamide (42): The
reaction of 1-bromo-2,4-difluorobenzene (0.193 g, 1 mmol), N-
(thiophen-2-ylmethyl)acetamide (0.310 g, 2 mmol) and KOAc
(0.196 g, 2 mmol) in the presence of Pd(OAc)2 (0.23 mg,
0.001 mmol) afforded 42 in 82% (0.219 g) yield. 1H NMR
(300 MHz, CDCl3): δ = 7.49–7.41 (m, 1 H, Ar), 7.15 (d, J = 3.0 Hz,
1 H, thiophene), 6.99–6.80 (m, 4 H, Ar and thiophene), 4.52 (d, J
= 5.8 Hz, 2 H, CH2), 1.98 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.2, 161.8 (dd, J = 249.9, 11.6 Hz), 158.5 (dd, J =
252.4, 11.7 Hz), 141.5, 135.5, 129.2 (dd, J = 9.4, 5.0 Hz), 126.7,
125.6 (d, J = 5.8 Hz), 118.4 (dd, J = 13.0, 4.0 Hz), 111.6 (dd, J =
21.5, 3.7 Hz), 104.3 (t, J = 26.1 Hz), 38.1, 22.7 ppm. C13H11F2NOS
(267.30): calcd. C 58.41, H 4.15; found C 58.60, H 4.27.
N-{2-[5-(4-Formylphenyl)thiophen-2-yl]ethyl}acetamide (47): The re-
action of 4-bromobenzaldehyde (0.185 g, 1 mmol), N-(thiophen-2-
ylethyl)acetamide (0.338 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) afforded 47 in
89% (0.243 g) yield. 1H NMR (300 MHz, CDCl3): δ = 9.95 (s, 1
H), 7.84 (d, J = 8.4 Hz, 2 H, Ar), 7.67 (d, J = 8.4 Hz, 2 H, Ar),
7.28 (d, J = 3.6 Hz, 1 H, thiophene), 6.85 (d, J = 3.6 Hz, 1 H,
thiophene), 5.95 (m, 1 H, NH), 3.56 (q, J = 6.6 Hz, 2 H, CH2),
3.06 (t, J = 6.6 Hz, 2 H, CH2), 1.99 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 191.4, 170.2, 143.5, 141.0, 140.0, 134.8,
130.4, 126.9, 125.5, 125.0, 40.7, 30.3, 23.2 ppm. C15H15NO2S
(273.35): calcd. C 65.91, H 5.53; found C 65.82, H 5.60.
tert-Butyl (Thiophen-2-ylmethyl)carbamate (43): (Thiophen-2-yl-
methyl)amine (1.1 mL, 8.7 mmol) was slowly added to a solution
of di-tert-butyl dicarbonate (2.1 mg, 9.6 mmol) and triethylamine
Eur. J. Org. Chem. 2010, 4412–4425
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4423

J. Roger, H. Doucet
FULL PAPER
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) X. Wang,
D. V. Gribkov, D. Sames, J. Org. Chem. 2007, 72, 1476; f) N.
Lebrasseur, I. Larrosa, J. Am. Chem. Soc. 2008, 130, 2926; g)
F. Bellina, S. Cauteruccio, A. Di Flore, R. Rossi, Eur. J. Org.
Chem. 2008, 5436; h) F. Bellina, S. Cauteruccio, A. Di Flore,
C. Marchietti, R. Rossi, Tetrahedron 2008, 64, 6060; i) S.-D.
Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew.
Chem. Int. Ed. 2008, 47, 1473; j) Y. Fall, H. Doucet, M. San-
telli, ChemSusChem 2009, 2, 153.
For recent examples of the palladium-catalysed direct 2- or 5-
arylation 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.[3a]; 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.
N-{2-[5-(p-Tolyl)thiophen-2-yl]ethyl}acetamide (48): The reaction of
4-bromotoluene (0.171 g, 1 mmol), N-[2-(thiophen-2-yl)ethyl]acet-
amide (0.338 g, 2 mmol) and K2CO3 (0.276 g, 2 mmol) in the pres-
ence of PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol) afforded 48 in 88%
(0.228 g) yield. 1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J =
8.4 Hz, 2 H, Ar), 7.16 (d, J = 8.4 Hz, 2 H, Ar), 7.09 (d, J = 3.6 Hz,
1 H, thiophene), 6.77 (d, J = 3.6 Hz, 1 H, thiophene), 5.78 (m, 1
H, NH), 3.54 (q, J = 6.6 Hz, 2 H, CH2), 3.00 (t, J = 6.6 Hz, 2 H,
CH2), 2.35 (s, 3 H, CH3), 1.97 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.1, 143.0, 140.4, 137.1, 131.5, 129.4,
126.1, 125.3, 122.2, 40.7, 30.0, 23.1, 31.1 ppm. C15H17NOS
(259.37): calcd. C 69.46, H 6.61; found C 69.60, H 6.67.
[4]
N-{2-[5-(2-Cyanophenyl)thiophen-2-yl]ethyl}acetamide (49): The re-
action of 2-bromobenzonitrile (0.182 g, 1 mmol), N-[2-(thiophen-
2-yl)ethyl]acetamide (0.338 g, 2 mmol) and KOAc (0.196 g,
2 mmol) in the presence of Pd(OAc)2 (0.23 mg, 0.001 mmol) af-
1
forded 49 in 91% (0.246 g) yield. H NMR (300 MHz, CDCl3): δ
= 7.67 (d, J = 8.4 Hz, 1 H, Ar), 7.60–7.50 (m, 2 H, Ar), 7.42 (d, J
= 3.6 Hz, 1 H, thiophene), 7.40–7.30 (m, 1 H, Ar), 6.83 (d, J =
3.6 Hz, 1 H, thiophene), 6.12 (m, 1 H, NH), 3.52 (q, J = 6.6 Hz, 2
H, CH2), 3.02 (t, J = 6.6 Hz, 2 H, CH2), 1.96 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.8, 144.0, 137.7, 137.5, 134.3,
133.1, 129.6, 127.6, 127.4, 126.5, 119.0, 109.3, 40.8, 30.0, 23.1 ppm.
C15H14N2OS (270.35): calcd. C 66.64, H 5.22; found C 66.51, H
5.30.
2008, 73, 7383; i) J. Roger, F. Pozgan, H. Doucet, J. Org. Chem.
ˇ
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-{2-[5-(Pyridin-3-yl)thiophen-2-yl]ethyl}acetamide (50): The reac-
tion of 3-bromopyridine (0.157 g, 1 mmol), N-[2-(thiophen-2-yl)-
ethyl]acetamide (0.338 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in
the presence of Pd(OAc)2 (1.2 mg, 0.005 mmol) afforded 50 in 84%
(0.207 g) yield. 1H NMR (300 MHz, CDCl3): δ = 8.71 (s, 1 H,
pyridine), 8.41 (d, J = 3.4 Hz, 1 H, pyridine), 7.75 (d, J = 7.9 Hz,
1 H, pyridine), 7.26 (dd, J = 7.9, 3.4 Hz, 1 H, pyridine), 7.14 (d, J
= 3.6 Hz, 1 H, thiophene), 6.80 (d, J = 3.6 Hz, 1 H, thiophene),
6.52 (m, 1 H, NH), 3.52 (q, J = 6.6 Hz, 2 H, CH2), 3.02 (t, J =
6.6 Hz, 2 H, CH2), 1.96 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.4, 147.6, 146.0, 142.6, 138.3, 132.6, 130.4, 126.5,
124.1, 123.6, 40.7, 30.0, 23.0 ppm. C13H14N2OS (246.33): calcd. C
63.39, H 5.73; found C 63.47, H 5.87.
[5]
For recent examples of the palladium-catalysed direct arylation
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) A. Battace, M.
Lemhadri, T. Zair, H. Doucet, M. Santelli, Adv. Synth. Catal.
2007, 349, 2507; e) F. Derridj, A. L. Gottumukkala, S. Djebbar,
H. Doucet, Eur. J. Inorg. Chem. 2008, 2550; f) M. Nakano, H.
Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1851; g) J. J.
Dong, J. Roger, H. Doucet, Tetrahedron Lett. 2009, 50, 2778;
h) J. Roger, F. Pozgan, H. Doucet, Green Chem. 2009, 11, 425.
ˇ
[6]
For recent examples of the palladium-catalysed direct arylation
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) J. J. Dong, J. Roger, F. Pozgan,
H. Doucet, Green Chem. 2009, 11, 1832; g) B. Liégaut, D. La-
pointe, L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009,
74, 1826; h) M. Ionita, J. Roger, H. Doucet, ChemSusChem
2010, 3, 367; i) J. Roger, F. Pozgan, H. Doucet, Adv. Synth.
Catal. 2010, 352, 696.
Acknowledgments
J.R. is grateful to the “Ministère de la Recherche” for a grant. We
thank Centre National de la Recherche Scientifique (CNRS) and
“Rennes Metropole” for providing financial support.
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4424
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4412–4425

Pd-Catalysed Direct 5-Arylation of Furfurylamine or 2-(Aminoalkyl)thiophenes
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Received: March 16, 2010
Published Online: June 29, 2010
Eur. J. Org. Chem. 2010, 4412–4425
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4425