Palladium-catalysed direct heteroarylation of bromobenzylacetamide derivatives: A simple access to heteroarylated benzylamine derivatives

Article abstract of DOI:10.1055/s-0029-1218814

The palladium-catalysed direct arylation of bromobenzylacetamide derivatives using a wide variety of heteroaromatics gives a very simple access to heteroarylated benzylacetamides. 2-, 3- and 4-Bromobenzylacetamides present a very similar reactivity. In the presence of 2-subtituted furans, thiophenes, pyrroles, thiazoles, or imidazoles a regioselective 5-arylation was observed. The reaction of benzoxazole gave the 2-arylated compounds; whereas 3,5-dimethylisoxazole gave the 4-arylated products. In most cases, the system using PdCl(C(dppb) as the catalyst, KOAc as the base, and DMAC as the solvent gave high yields of coupling products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218814

PAPER
2553
Palladium-Catalysed Direct Heteroarylation of Bromobenzylacetamide
Derivatives: A Simple Access to Heteroarylated Benzylamine Derivatives
D
irec
t
H
eteroaryla
o
tionof
B
rom
u
obenzylaceta
r
mide
D
e
i
rivativ
a
es Laidaoui,a,b Abdellah Miloudi,b Douniazad El Abed,*b Henri Doucet*a
a
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes ‘Catalyse et Organometalliques’, Campus de Beaulieu,
35042 Rennes, France
Fax +33(2)23236939; E-mail: henri.doucet@univ-rennes1.fr
Laboratoire de Réactivité et Chimie Fine, Département de Chimie, Faculté des Sciences, Université d’Oran Es-Sénia, BP. 1524,
EL M’naouer Oran 31100, Algeria
b
Received 23 March 2010; revised 31 March 2010
One of the most classical methods to synthesise biaryl de-
rivatives is to employ an aryl halide with an organometal-
lic aryl derivative using a palladium catalyst.1 However,
these reactions require the preliminary preparation of or-
Abstract: The palladium-catalysed direct arylation of bromoben-
zylacetamide derivatives using a wide variety of heteroaromatics
gives a very simple access to heteroarylated benzylacetamides. 2-,
3- and 4-Bromobenzylacetamides present a very similar reactivity.
In the presence of 2-subtituted furans, thiophenes, pyrroles, thia- ganometallic derivatives such as ArB(OR)2, ArZnX,
zoles, or imidazoles a regioselective 5-arylation was observed. The
ArMgX, or ArSnR3 and provide either an organometallic
reaction of benzoxazole gave the 2-arylated compounds; whereas
or a salt (MX) as by-product.
3,5-dimethylisoxazole gave the 4-arylated products. In most cases,
Since the reports by Ohta and co-workers on the palladi-
um-catalysed coupling of aryl halides with heteroaryl de-
rivatives via a C–H bond activation,2 very exciting results
for the coupling of a variety of heteroaryl derivatives with
aryl halides have been reported by several groups.3–10
However, to our knowledge, the direct coupling of het-
eroaromatics with halobenzylacetamide derivatives via a
C–H bond activation/functionalisation has attracted much
less attention. A few intramolecular direct arylations
using quite similar compounds have been reported
(Scheme 1, top).11 Some examples of intermolecular di-
rect arylation of benzamide, via a C–H bond activation at
carbon C-2 of this reactant, have also been described
(Scheme 1, bottom).12
the system using PdCl(C3H5)(dppb) as the catalyst, KOAc as the
base, and DMAC as the solvent gave high yields of coupling prod-
ucts.
Key words: palladium, cross-coupling reaction, arylation, furans,
thiophenes, pyrroles, thiazoles, imidazoles, benzoxazoles
Both benzylamine and heteroaromatic derivatives often
present useful biological properties. As some substituted
benzylamine derivatives have already been found to show
powerful bioactivities (Figure 1), we assumed that the dis-
covery of a simple procedure for the preparation of a large
variety of heteroarylated benzylamine derivatives could
be useful for pharmaceutical researchers.
CO2Me
CO2Me
HN
N
N
O
N
N
N
[Pd]
N
R
R
direct arylation
O
I
HO2C
N
valsartan
O
O
NR2
Ar
NR2
H
[Pd]
Me
+ ArX
N
CO2Me
direct arylation
fexaramine
Me
CO2H
O
Scheme 1
O
N
H
On the other hand, to the best of our knowledge, no inter-
molecular examples of palladium-catalysed coupling of
benzylacetamide derivatives with aryl halides (Scheme 2,
top), or of coupling of halobenzylacetamide derivatives
with heteroaromatics (Scheme 2, bottom) have been de-
scribed. To date, the Suzuki coupling reaction remains the
most classical method to prepare arylated benzylacet-
amide derivatives.13
N
repaglinide
Figure 1 Benzylamine derivatives of biological interest
SYNTHESIS 2010, No. 15, pp 2553–2566
x
x.
x
x
.
2
0
1
0
Advanced online publication: 15.06.2010
DOI: 10.1055/s-0029-1218814; Art ID: Z07710SS
© Georg Thieme Verlag Stuttgart · New York

2554
N. Laidaoui et al.
PAPER
R2
O
O
O
R
R
R1
NH
R1
O
NH
H
NH
Ar
NH2
[Pd]
+ ArX
CH2Cl2, 25 °C, 2 h
Et3N
Cl
R2
direct arylation
+
Br
Br
1–5
O
O
Scheme 3
R
R
NH
NH
[Pd]
+ HetArH
Then, we studied the reactivity of these bromobenzyl-
acetamide derivatives in the presence of furan derivatives
(Scheme 4, Table 1). As these aryl bromides are not elec-
tron-deficient, their oxidative addition to palladium
should be relatively slow. Therefore, for these reaction,
we selected PdCl(C3H5)(dppb) [dppb: 1,4-bis(diphe-
nylphosphino)butane] as the catalyst precursor.4f
direct arylation
Br
HetAr
Scheme 2
Here, we wish to report on the palladium-catalysed direct
arylation of a set of heteroaromatics using 2-, 3-, and 4-
bromobenzylacetamide derivatives as the coupling part-
ners.
R3
NH
O
R2
R3
O
The bromobenzylacetamide derivatives 1–5 were pre-
pared in high yields using 2-, 3-, and 4-bromobenzyl-
amines and acyl chlorides as the reaction partners in the
presence of triethylamine (Scheme 3).
R2
R1
R1
NH
PdCl(C3H5)(dppb) (2 mol%)
KOAc, DMAc, 150 °C, 20 h
+
O
O
Br
6–14
Scheme 4
Table 1 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Furan Derivatives (Scheme 5)a
Entry
Aryl bromide
Heteroarene
Product
Yield (%)b
O
O
NH
1
76
HN
Br
O
O
1
6
HN
O
O
2
3
78
79
HN
O
O
O
Br
2
7
O
Br
O
HN
HN
O
3
8
O
O
4
53
NH
HN
O
Br
Ph
4
O
9
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

PAPER
Direct Heteroarylation of Bromobenzylacetamide Derivatives
2555
Table 1 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Furan Derivatives (Scheme 5)a (continued)
Entry
Aryl bromide
Heteroarene
Product
Yield (%)b
O
NH
O
5
75
76
HN
Br
O
O
O
1
O
10
O
HN
Br
O
O
6
HN
O
O
O
3
O
11
O
CO2Me
Br
CO2Me
HN
7
8
71
62
HN
O
O
3
12
O
O
NH
OH
HN
Br
O
OH
O
1
13
O
Br
O
HN
9
79
HN
O
O
3
14
a Reaction conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1 mmol), furan derivative (2 mmol), KOAc (2 mmol), DMAC, 20 h,
150 °C.
b Isolated yields.
Me
In the presence of 2-bromobenzylacetamide and 2-n-bu-
O
N
tylfuran, using dimethylacetamide (DMAC) as the sol-
vent, KOAc as the base, and 2 mol% PdCl(C3H5)(dppb),
a very regioselective 5-arylation of this furan derivative
was observed and 6 was obtained in high yield (Scheme 4,
Table 1, entry 1). Then, we tried to evaluate the scope and
limitations of this procedure with [PdCl(C3H5)(dppb) as
the catalyst, KOAc as the base, and DMAC as the solvent
at 150 °C] using several furan derivatives (Scheme 4,
Table 1). The reaction of 3- and 4-bromobenzylacetamide
derivatives 2 and 3 with 2-n-butylfuran gave 7 and 8 in 78
and 79% yield, respectively (Table 1, entries 2 and 3).
O
R
NMe
Br
[Pd]
R
t-BuOK
OBn
OBn
Scheme 5
Using our reaction conditions, such intramolecular reac-
tion was not observed, and the expected product 9 was ob-
tained in 53% yield (Table 1, entry 4). This moderate
yield was due to a partial conversion of this aryl bromide,
and not to the formation of intramolecular cyclised prod-
uct. 1-(Furan-2-yl)butan-1-one is also a highly reactive
substrate for this reaction, and the coupling with 1 and 3
gave 10 and 11, respectively, in good yields (Table 1, en-
tries 5 and 6). In the presence of methyl 2-methylfuran-3-
In the presence of N-(2-bromobenzyl)-2-phenylacetamide
(4), an intramolecular cyclisation could occur. Such palla-
dium-catalysed intramolecular reaction has already been
observed with the strong base, t-BuOK (Scheme 5).14
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2556
N. Laidaoui et al.
PAPER
R3
NH
O
R3
Br
O
R2
R2
NH
PdCl(C3H5)(dppb) (2 mol%)
KOAc, DMAC, 150 °C, 20 h
+
R1
R1
S
S
15–24
Scheme 6
carboxylate, the expected 5-arylated furan 12 was pro- Next, we examined the coupling of thiophene derivatives
duced in 71% yield (Table 1, entry 7).
with four bromobenzylacetamide derivatives (Scheme 6,
Table 2). As expected, the reaction of 2-n-butylthiophene
with 1–3 gave the coupling products 15–17 in good yields
(Table 2, entries 1–3). Again, the reaction was found to be
completely regioselective, and only the formation of the
5-arylated thiophenes was detected.
The direct use of some furan derivatives in organic syn-
thesis, such as furfuryl alcohol, is an important field of re-
search in green chemistry, since they can be obtained from
agricultural wastes rich in pentosan polymers. Moreover,
the use of heteroaromatics bearing unprotected functions
would be very useful since it would allow to avoid the pro- Very clean reactions were also observed in the presence of
tection/deprotection sequence, and therefore should pro- 2-methyl-2-thiophen-2-yl[1,3]dioxolane to give the corre-
vide a more environmentally and economically attractive sponding 5-arylated thiophenes 18–20 in 67–79% yields
access to such arylated heteroaromatics. In the presence of (Table 2, entries 4–6). It should be noted that the protec-
1, furfuryl alcohol, was regioselectively arylated at C-5, tion of the acetyl function is not essential for this reaction.
and 13 was obtained in 62% yield (Table 1, entry 8).
The use of 2-acetylthiophene and 2-propionylthiophene
also gave the desired coupling products 21 and 22, respec-
tively, in high yields (Table 2, entries 7 and 8).
Thiophene-2-carbonitrile was also found to be a suitable
reactant for this reaction (Table 2, entries 9 and 10).
In order to determine the reactivity a 2-substituted benzo-
furan derivative for palladium-catalysed direct arylations
with bromobenzylacetamide derivatives, we examined
the arylation of 2-ethylbenzofuran4g with 3. As expected,
a regioselective 3-arylation of this benzofuran was ob-
served to produce 14 in 79% yield (Table 1, entry 9).
Table 2 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Thiophene Derivatives (Scheme 6)a
Entry
1
Aryl bromide
Heteroarene
Product
Yield (%)b
O
O
NH
75
HN
Br
S
S
1
15
HN
O
O
2
3
80
73
HN
S
S
S
Br
2
16
O
Br
O
HN
HN
S
3
17
O
NH
O
O
4
71
HN
S
Br
O
O
S
1
O
18
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

PAPER
Direct Heteroarylation of Bromobenzylacetamide Derivatives
2557
Table 2 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Thiophene Derivatives (Scheme 6)a (continued)
Entry
Aryl bromide
Heteroarene
Product
Yield (%)b
O
NH
O
O
HN
Br
5
67
S
O
O
S
5
O
19
HN
O
O
O
6
7
79
76
HN
O
S
S
Br
O
O
2
20
O
HN
Br
O
O
HN
S
O
S
3
21
O
HN
Br
O
O
8
79
HN
S
S
3
O
22
O
O
NH
9
65
54
HN
CN
S
Br
S
1
CN
23
O
Br
O
HN
10
HN
CN
S
S
CN
3
24
a Reaction conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1 mmol), thiophene derivative (2 mmol), KOAc (2 mmol), DMAC, 20 h,
150 °C.
b Isolated yields.
The direct arylation of pyrrole derivatives also proceeds in Under these conditions, the coupling reaction with 3 gave
good yields (Scheme 7, Table 3). The reaction of 2- the expected 2-arylated compound 30 in 73% yield
formylpyrrole and 2-acetylpyrrole with 1–3 gave 25–28 in (Table 3, entry 6).
good yields. Again, the reaction was found to be very re-
gioselective in favor of the 5-arylation. Even methyl 1-
methylpyrrole-2-carboxylate can be employed. No decar-
The coupling of a 2-substituted thiazole with aryl bro-
mides 1–3 is shown in Scheme 8 and the results are pro-
vided in Table 4. In all cases, the regioselective 5-
boxylation of this substrate was observed in the course of
arylation of this substrate was observed, and the products
the reaction with 1, and 29 was obtained in 65% yield
31–33 were obtained in good yields. On the other hand,
the coupling with 1,2-dimethylimidazole with 2 gave 34
in only 47% yield due to a moderate conversion of the aryl
(Table 3, entry 5). We also employed 1-methylpyrrole as
the coupling partner. As the formation of the 2,5-diarylat-
ed pyrrole as side-product is possible with this substrate,
bromide (Table 4, entry 4).
we employed a larger excess of this reactant (4 equiv).
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

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Table 3 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Pyrrole Derivatives (Scheme 7)a
Entry
Aryl bromide
Heteroarene
Product
Yield (%)b
O
NH
O
1
73
CHO
N
HN
Br
O
Me
N
1
Me
25
O
Br
O
HN
2
3
4
70
81
66
CHO
N
HN
O
N
Me
3
Me
26
HN
O
O
O
HN
N
O
N
Me
Br
Me
2
27
O
HN
Br
O
O
HN
N
O
N
Me
Me
3
28
O
NH
O
O
5
6
65
HN
N
Br
OMe
O
N
Me
1
Me
MeO
29
O
Br
O
HN
73c
HN
N
N
Me
3
Me
30
a Reaction conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1 mmol), pyrrole derivative (2 mmol), KOAc (2 mmol), DMAC, 20 h,
150 °C.
b Isolated yields.
c Excess of 1-methylpyrrole (4 mmol) was used.
R3
NH
O
R2
R3
Br
O
R2
NH
PdCl(C3H5)(dppb) (2 mol%)
KOAc, DMAC, 150 °C, 20 h
+
R1
R1
N
N
Me
Me
25–30
Scheme 7
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

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Direct Heteroarylation of Bromobenzylacetamide Derivatives
2559
Table 4 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Thiazole, Imidazole, and Isoxazole Derivatives (Schemes 8
and 9)a
Entry
Aryl bromide
Heteroarene
Product
Yield (%)b
O
O
NH
N
S
1
72
HN
Br
N
S
1
31
HN
O
O
N
S
N
2
3
67
81
HN
S
Br
2
32
O
Br
O
N
S
HN
N
HN
S
3
33
HN
O
N
O
O
N
4
5
47
73
HN
HN
N
N
Br
Me
Me
2
34
HN
O
N
O
N
O
Br
2
35
O
Br
O
HN
N
O
6
80
HN
N
O
3
36
a Reaction conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1 mmol), thiazole, imidazole, or isoxazole derivative (2 mmol), KOAc (2
mmol), DMAC, 20 h, 150 °C.
b Isolated yields.
R3
NH
The direct arylation of 3,5-dimethyloxazole was then ex-
amined, and the expected 4-arylation products 35 and 36
were obtained in good yields (Scheme 9, Table 4).
O
R3
O
R2
PdCl(C3H5)(dppb) (2 mol%)
R2
N
N
NH
+
Finally, we studied the coupling of the aryl bromides 1–3
with benzoxazole (Scheme 10, Table 5). We had previ-
R1
R1
or NMe
KOAc, DMAC, 150 °C, 20 h
S
S
Br
or NMe
31–34
R3
Br
N
O
Scheme 8
R2
R3
NH
NH
O
R3
NH
O
R2
O
R2
N
PdCl(C3H5)(dppb) (2 mol%)
KOAc, DMAC, 150 °C, 20 h
R2
R1
N
+
NH
PdCl(C3H5)(dppb) (2 mol%)
KOAc, DMAC, 150 °C, 20 h
O
+
O
N
O
Br
37–39
35, 36
O
Scheme 9
Scheme 10
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N. Laidaoui et al.
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Table 5 Palladium-Catalysed Reaction of N-(Bromobenzyl)alkylamides with Benzoxazole (Scheme 10)a
Entry
1
Aryl bromide
Product
Yield (%)b
O
O
NH
80
HN
Br
N
1
O
37
HN
O
O
N
O
2
3
78
76
HN
Br
2
38
O
Br
O
HN
N
O
HN
3
39
a Reaction conditions: PdCl(C3H5)(dppb): 0.02 mmol, aryl bromide (1 mmol), benzoxazole (2 mmol), KOAc (2 mmol), DMAC, 20 h, 150 °C.
b Isolated yields.
N-(2-Bromobenzyl)propionamide (1)
2-Bromobenzylamine (0.558 g, 3 mmol) and propionyl chloride
(0.555 g, 6 mmol) gave 1 in 70% yield (0.508 g).
1H NMR (200 MHz, CDCl3): d = 7.63 (d, J = 7.8 Hz, 1 H), 7.45–
7.20 (m, 2 H), 7.18 (t, J = 7.6 Hz, 1 H), 6.10 (m, 1 H), 4.50 (d,
J = 5.9 Hz, 2 H), 2.25 (q, J = 7.5 Hz, 2 H), 1.20 (t, J = 7.5 Hz, 3 H).
ously observed that the direct arylation of electron-defi-
cient aryl bromides with benzoxazole often led to
moderate yields of coupling products, when the reactions
were performed at elevated temperature; whereas the re-
actions performed with quite electron-rich aryl bromides
gave high yield of desired product even for the reactions
performed at 150 °C. Therefore, as 1–3 are not electron-
deficient, we performed the reactions at 150 °C, and as ex-
pected, in all cases the 2-arylated benzoxazoles 37–39
were obtained in high yields.
13C NMR (50 MHz, CDCl3): d = 174.1, 137.8, 133.2, 130.8, 129.6,
128.2, 124.2, 44.2, 30.1, 10.2.
Anal. Calcd for C10H12BrNO: C, 49.61; H, 5.00. Found: C, 49.54;
H, 5.12.
In summary, bromobenzylacetamides are useful reactants
in palladium-catalysed direct arylation using several het-
eroaryl derivatives. The use of 2 mol% PdCl(C3H5)(dppb)
with KOAc as the base and DMAC as the solvent gener-
ally led to high yields of the heteroarylated benzylacet-
amides. 2-, 3- and 4-Bromobenzylacetamides show a
similar reactivity. This procedure is economically attrac-
tive due to the easy access of several bromobenzylamines
and heteroaromatics, and also due to the reduction of
number of steps to prepare these compounds.
N-(3-Bromobenzyl)propionamide (2)
3-Bromobenzylamine (0.558 g, 3 mmol) and propionyl chloride
(0.555 g, 6 mmol) gave 2 in 72% yield (0.523 g).
1H NMR (200 MHz, CDCl3): d = 7.45–7.10 (m, 4 H), 6.20 (m, 1 H),
4.42 (d, J = 5.9 Hz, 2 H), 2.25 (q, J = 7.5 Hz, 2 H), 1.20 (t, J = 7.5
Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 174.9, 141.6, 131.0, 130.9, 130.7,
126.4, 122.8, 43.0, 29.7, 10.4.
Anal. Calcd for C10H12BrNO: C, 49.61; H, 5.00. Found: C, 49.63;
H, 5.12.
N-[1-(4-Bromophenyl)ethyl]propionamide (3)
1-(4-Bromophenyl)ethylamine (0.600 g, 3 mmol) and propionyl
chloride (0.555 g, 6 mmol) gave 3 in 72% yield (0.553 g).
1H NMR (200 MHz, CDCl3): d = 7.48 (d, J = 8.5 Hz, 2 H), 7.18 (d,
J = 8.5 Hz, 2 H), 5.60 (m, 1 H), 5.10 (m, 1 H), 2.27 (q, J = 7.5 Hz,
2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.20 (t, J = 7.5 Hz, 3 H).
All reactions were run under argon using vacuum lines and oven-
dried Schlenk tubes. Commercial heteroaromatics, analytical grade
DMAC, Pd(OAc)2, and KOAc (99%) were employed without puri-
1
fication. H (200 MHz), 13C (50 MHz) spectra were recorded in
CDCl3. Chemical shifts (d) are reported in ppm relative to CDCl3
(1H: 7.25 and 13C: 77.0). Flash chromatography was performed on
silica gel (230–400 mesh).
13C NMR (50 MHz, CDCl3): d = 173.4, 142.9, 132.1, 128.3, 121.5,
48.5, 30.1, 22.2, 10.2.
N-Bromobenzylacetamide Derivatives; General Procedure
An oven-dried 100 mL flask equipped with a magnetic stirring bar
under argon atmosphere was charged with the aryl bromide (3
mmol), the acyl chloride (6 mmol), Et3N (6 mL) and anhyd CH2Cl2
(50 mL) and the mixture was stirred at r.t. for 2 h. Then, H2O (50
mL) was added and the mixture was extracted with CH2Cl2 (3 × 20
mL). The product obtained after evaporation of the solvent was pu-
rified by bulb to bulb distillation.
Anal. Calcd for C11H14BrNO: C, 51.58; H, 5.51. Found: C, 51.40;
H, 5.37.
N-(2-Bromobenzyl)-2-phenylacetamide (4)
2-Bromobenzylamine (0.558 g, 3 mmol) and phenylacetyl chloride
(0.928 g, 6 mmol) gave 4 in 66% yield (0.602 g).
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Direct Heteroarylation of Bromobenzylacetamide Derivatives
2561
1H NMR (200 MHz, CDCl3): d = 7.55–7.00 (m, 9 H), 6.00 (m, 1 H),
4.45 (d, J = 5.9 Hz, 2 H), 3.58 (s, 2 H).
13C NMR (50 MHz, CDCl3): d = 170.9, 137.1, 134.7, 132.7, 130.0,
129.5, 129.1, 129.0, 127.6, 127.4, 123.6, 43.9, 43.7.
13C NMR (50 MHz, CDCl3): d = 173.7, 156.7, 151.7, 138.7, 131.6,
129.0, 126.1, 122.6, 122.4, 106.9, 106.0, 43.6, 30.2, 29.7, 22.2,
13.8, 9.9.
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12. Found: C, 75.57; H,
8.09.
Anal. Calcd for C15H14BrNO: C, 59.23; H, 4.63. Found: C, 59.40;
H, 4.47.
N-{1-[4-(5-Butylfuran-2-yl)phenyl]ethyl}propionamide (8)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 2-
n-butylfuran (0.248 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 8
in 79% yield (236 mg).
1H NMR (200 MHz, CDCl3): d = 7.55 (d, J = 8.2 Hz, 2 H), 7.32 (d,
J = 8.2 Hz, 2 H), 6.50 (d, J = 3.1 Hz, 1 H), 6.02 (d, J = 3.1 Hz, 1 H),
5.80 (m, 1 H), 4.12 (m, 1 H), 2.70 (t, J = 7.6 Hz, 2 H), 2.20 (q,
J = 7.6 Hz, 2 H), 1.68 (m, 2 H), 1.42 (d, J = 7.6 Hz, 3 H), 1.40 (m,
2 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H).
N-(2-Bromobenzyl)isobutyramide (5)
2-Bromobenzylamine (0.558 g, 3 mmol) and isobutyryl chloride
(0.639 g, 6 mmol) gave 5 in 68% yield (0.522 g).
1H NMR (200 MHz, CDCl3): d = 7.60 (d, J = 7.8 Hz, 1 H), 7.45–
7.20 (m, 2 H), 7.12 (t, J = 7.6 Hz, 1 H), 5.90 (m, 1 H), 4.50 (d,
J = 5.9 Hz, 2 H), 2.38 (sept, J = 7.5 Hz, 1 H), 1.15 (d, J = 7.5 Hz, 6
H).
13C NMR (50 MHz, CDCl3): d = 177.1, 137.8, 133.2, 130.8, 129.5,
128.2, 124.1, 44.1, 36.0, 20.0.
13C NMR (50 MHz, CDCl3): d = 171.8, 155.4, 150.7, 140.6, 129.3,
125.4, 122.5, 105.8, 104.6, 47.3, 29.1, 28.7, 26.8, 21.2, 20.5, 12.8,
8.8.
Anal. Calcd for C11H14BrNO: C, 51.58; H, 5.51. Found: C, 51.43;
H, 5.45.
Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42. Found: C, 76.14; H,
8.50.
PdCl(dppb)(C3H5)
An oven-dried 40 mL Schlenk tube equipped with a magnetic stir-
ring bar under argon atmosphere was charged with [Pd(C3H5)Cl]2
(182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). Anhyd CH2Cl2 (10
mL) was added and the mixture was stirred at r.t. for 20 min. The
solvent was removed in vacuum. The yellow powder obtained was
used without purification.
N-[2-(5-Butylfuran-2-yl)benzyl]-2-phenylacetamide (9)
N-(2-Bromobenzyl)-2-phenylacetamide (4; 0.304 g, 1 mmol), 2-n-
butylfuran (0.248 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 9
in 53% yield (184 mg).
1H NMR (200 MHz, CDCl3): d = 7.55 (d, J = 7.6 Hz, 1 H), 7.50–
7.20 (m, 8 H), 6.40 (d, J = 3.1 Hz, 1 H), 6.05 (d, J = 3.1 Hz, 1 H),
5.90 (m, 1 H), 4.58 (d, J = 5.6 Hz, 2 H), 3.59 (s, 2 H), 2.53 (t, J = 7.6
Hz, 2 H), 1.60 (m, 2 H), 1.40 (m, 2 H), 0.96 (t, J = 7.6 Hz, 3 H).
31P NMR (81 MHz, CDCl3): d = 19.3 (s).
Palladium-Catalysed Couplings of Heteroaromatics with
N-Bromobenzylacetamide Derivatives; General Procedure
The aryl bromide (1 mmol), heteroaryl derivative (2 mmol), KOAc
(0.196 g, 2 mmol), and PdCl(C3H5)(dppb) (0.012 g, 0.02 mmol)
were dissolved in DMAC (3 mL) under argon. The reaction mixture
was stirred at 150 °C for 20 h. The solvent was removed in vacuo,
and then the product was purified by silica gel column chromatog-
raphy.
13C NMR (50 MHz, CDCl3): d = 171.1, 157.1, 135.2, 134.4, 130.6,
129.9, 129.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 109.5, 107.1,
44.3, 43.2, 30.4, 28.2, 22.7, 14.3.
Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25. Found: C, 79.40; H,
7.25.
N-[2-(5-Butylfuran-2-yl)benzyl]propionamide (6)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 2-n-bu-
tylfuran (0.248 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 6
in 76% yield (217 mg).
1H NMR (200 MHz, CDCl3): d = 7.62 (d, J = 7.6 Hz, 1 H), 7.50–
7.20 (m, 3 H), 6.47 (d, J = 3.1 Hz, 1 H), 6.12 (d, J = 3.1 Hz, 1 H),
5.90 (m, 1 H), 4.62 (d, J = 5.6 Hz, 2 H), 2.73 (t, J = 7.6 Hz, 2 H),
2.24 (q, J = 7.6 Hz, 2 H), 1.68 (m, 2 H), 1.40 (m, 2 H), 1.20 (t,
J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H).
N-[2-(5-Butyrylfuran-2-yl)benzyl]propionamide (10)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 1-furan-2-
ylbutan-1-one (0.276 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 10
in 75% yield (225 mg).
1H NMR (200 MHz, CDCl3): d = 7.62 (d, J = 8.2 Hz, 2 H), 7.40–
7.20 (m, 4 H), 6.93 (m, 1 H), 6.73 (d, J = 3.1 Hz, 1 H), 4.53 (d,
J = 5.6 Hz, 2 H), 2.81 (t, J = 7.6 Hz, 2 H), 2.28 (q, J = 7.6 Hz, 2 H),
1.82 (m, 2 H), 1.17 (t, J = 7.6 Hz, 3 H), 1.00 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 189.3, 174.4, 158.3, 152.1, 136.6,
132.5, 130.2, 129.0, 128.8, 128.2, 119.6, 109.9, 43.9, 40.5, 30.1,
18.5, 14.3, 10.0.
13C NMR (50 MHz, CDCl3): d = 173.3, 156.6, 151.3, 134.1, 130.4,
130.2, 127.8, 127.7, 127.6, 109.1, 106.9, 42.6, 30.2, 29.7, 27.8,
22.2, 13.8, 9.7.
Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07. Found: C, 72.14; H,
7.24.
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12. Found: C, 75.64; H,
8.04.
N-{1-[4-(5-Butyrylfuran-2-yl)phenyl]ethyl}propionamide (11)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 1-
furan-2-ylbutan-1-one (0.276 g, 2 mmol), KOAc (0.196 g, 2 mmol),
and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave
11 in 76% yield (238 mg).
1H NMR (200 MHz, CDCl3): d = 7.70 (d, J = 8.2 Hz, 2 H), 7.32 (d,
J = 8.2 Hz, 2 H), 7.21 (d, J = 3.1 Hz, 1 H), 6.70 (d, J = 3.1 Hz, 1 H),
6.30 (m, 1 H), 5.12 (m, 1 H), 2.82 (t, J = 7.6 Hz, 2 H), 2.20 (q,
J = 7.6 Hz, 2 H), 1.78 (m, 2 H), 1.45 (d, J = 7.6 Hz, 2 H), 1.15 (t,
J = 7.6 Hz, 3 H), 0.98 (t, J = 7.6 Hz, 3 H).
N-[3-(5-Butylfuran-2-yl)benzyl]propionamide (7)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 2-n-bu-
tylfuran (0.248 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 7
in 78% yield (222 mg).
1H NMR (200 MHz, CDCl3): d = 7.60–7.00 (m, 4 H), 6.55 (d,
J = 3.1 Hz, 1 H), 6.05 (d, J = 3.1 Hz, 1 H), 5.70 (m, 1 H), 4.45 (d,
J = 5.6 Hz, 2 H), 2.72 (t, J = 7.6 Hz, 2 H), 2.26 (q, J = 7.6 Hz, 2 H),
1.68 (m, 2 H), 1.40 (m, 2 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6
Hz, 3 H).
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

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N. Laidaoui et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 189.7, 173.4, 157.6, 152.2, 145.0,
128.8, 127.1, 125.6, 119.6, 107.7, 48.7, 40.7, 30.1, 22.1, 18.4, 14.3,
10.2.
13C NMR (50 MHz, CDCl3): d = 173.9, 147.0, 139.2, 136.6, 134.8,
131.4, 129.8, 128.5, 127.9, 126.8, 124.8, 42.3, 34.2, 30.2, 30.1,
22.7, 14.3, 10.2.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40. Found: C, 72.90; H,
7.31.
Anal. Calcd for C18H23NOS: C, 71.72; H, 7.69. Found: C, 71.80; H,
7.80.
Methyl 2-Ethyl-5-[4-(1-propionylaminoethyl)phenyl]furan-3-
carboxylate (12)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol),
methyl 2-methylfuran-3-carboxylate (0.280 g, 2 mmol), KOAc
(0.196 g, 2 mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in
DMAC (3 mL) gave 12 in 71% yield (224 mg).
1H NMR (200 MHz, CDCl3): d = 7.58 (d, J = 8.2 Hz, 2 H), 7.31 (d,
J = 8.2 Hz, 2 H), 6.83 (s, 1 H), 5.74 (m, 1 H), 5.12 (m, 1 H), 3.83 (s,
3 H), 2.63 (s, 3 H), 2.20 (q, J = 7.6 Hz, 2 H), 1.48 (d, J = 7.6 Hz, 2
H), 1.15 (t, J = 7.6 Hz, 3 H).
N-[3-(5-Butylthiophen-2-yl)benzyl]propionamide (16)
N-(3-Bromobenzyl)propionamide (2, 0.242 g, 1 mmol), 2-n-bu-
tylthiophene (0.280 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 16
in 80% yield (241 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.10 (m, 5 H), 6.74 (d,
J = 3.4 Hz, 1 H), 5.70 (m, 1 H), 4.45 (d, J = 5.6 Hz, 2 H), 2.83 (t,
J = 7.6 Hz, 2 H), 2.20 (q, J = 7.6 Hz, 2 H), 1.68 (m, 2 H), 1.40 (m,
2 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.6, 145.9, 141.0, 138.9, 135.1,
129.1, 126.3, 125.0, 124.8, 124.6, 122.9, 43.5, 33.7, 29.9, 29.7,
22.1, 13.8, 9.9.
13C NMR (50 MHz, CDCl3): d = 172.8, 164.4, 158.7, 151.5, 142.9,
129.1, 126.6, 123.9, 115.1, 105.4, 51.4, 48.3, 29.7, 21.6, 13.9, 9.8.
Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71. Found: C, 68.70; H,
6.87.
Anal. Calcd for C18H23NOS: C, 71.72; H, 7.69. Found: C, 71.59; H,
7.54.
N-[2-(5-Hydroxymethylfuran-2-yl)benzyl]propionamide (13)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), furfuryl
alcohol (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 13
in 62% yield (161 mg).
N-{1-[4-(5-Butylthiophen-2-yl)phenyl]ethyl}propionamide (17)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 2-
n-butylthiophene (0.280 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 17
in 73% yield (230 mg).
1H NMR (200 MHz, CDCl3): d = 7.62 (d, J = 8.2 Hz, 1 H), 7.40–
7.15 (m, 3 H), 6.48 (d, J = 3.1 Hz, 1 H), 6.34 (d, J = 3.1 Hz, 1 H),
5.70 (m, 1 H), 4.71 (d, J = 5.6 Hz, 2 H), 4.60 (s, 2 H), 3.95 (m, 1 H),
2.20 (q, J = 7.6 Hz, 2 H), 1.17 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 174.5, 155.1, 153.7, 134.6, 131.5,
130.4, 128.6, 128.5, 128.4, 109.6, 109.1, 57.5, 43.5, 30.1, 10.1.
1H NMR (200 MHz, CDCl3): d = 7.65 (d, J = 8.2 Hz, 2 H), 7.28 (d,
J = 8.2 Hz, 2 H), 7.15 (d, J = 3.4 Hz, 1 H), 6.72 (d, J = 3.4 Hz, 1 H),
5.80 (m, 1 H), 5.15 (m, 1 H), 2.83 (t, J = 7.6 Hz, 2 H), 2.18 (q,
J = 7.6 Hz, 2 H), 1.68 (m, 2 H), 1.50 (d, J = 7.5 Hz, 3 H), 1.40 (m,
2 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.0, 145.6, 142.9, 141.1, 133.8,
126.6, 125.7, 125.0, 122.7, 48.3, 33.7, 29.9, 29.6, 22.2, 21.7, 13.8,
9.8.
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61. Found: C, 69.50; H,
6.47.
Anal. Calcd for C19H25NOS: C, 72.34; H, 7.99. Found: C, 72.49; H,
7.87.
N-{1-[4-(2-Ethylbenzofuran-3-yl)phenyl]ethyl}propionamide
(14)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 2-
ethylbenzofuran (0.292 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 14
in 79% yield (254 mg).
1H NMR (200 MHz, CDCl3): d = 7.75–7.10 (m, 8 H), 5.70 (m, 1 H),
5.20 (m, 1 H), 2.88 (q, J = 7.6 Hz, 2 H), 2.20 (q, J = 7.6 Hz, 2 H),
1.45 (d, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H), 1.15 (t, J = 7.6
Hz, 3 H).
N-{2-[5-(2-Methyl[1,3]dioxolan-2-yl)thiophen-2-yl]benzyl}pro-
pionamide (18)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 2-methyl-
2-thiophen-2-yl[1,3]dioxolane (0.340 g, 2 mmol), KOAc (0.196 g,
2 mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 18 in 71% yield (235 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 7.05 (d,
J = 3.4 Hz, 1 H), 6.87 (d, J = 3.4 Hz, 1 H), 5.70 (m, 1 H), 4.50 (d,
J = 5.6 Hz, 2 H), 4.05 (m, 4 H), 2.18 (q, J = 7.6 Hz, 2 H), 1.82 (s, 3
H), 1.15 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.5, 147.7, 141.1, 136.3, 133.8,
131.0, 129.2, 128.4, 127.5, 126.5, 124.4, 107.0, 41.7, 29.6, 27.5,
9.9.
13C NMR (50 MHz, CDCl3): d = 172.6, 156.3, 154.0, 142.0, 131.9,
129.6, 128.7, 126.6, 123.6, 122.6, 119.4, 115.7, 110.8, 48.4, 29.8,
21.7, 20.2, 12.9, 9.8.
Anal. Calcd for C21H23NO2: C, 78.47; H, 7.21. Found: C, 78.31; H,
7.12.
Anal. Calcd for C18H21NO3S: C, 65.23; H, 6.39. Found: C, 65.41; H,
6.24.
N-[2-(5-Butylthiophen-2-yl)benzyl]propionamide (15)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 2-n-bu-
tylthiophene (0.280 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 15
in 75% yield (226 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 6.80 (d,
J = 3.4 Hz, 1 H), 6.74 (d, J = 3.4 Hz, 1 H), 5.70 (m, 1 H), 4.55 (d,
J = 5.6 Hz, 2 H), 2.83 (t, J = 7.6 Hz, 2 H), 2.18 (q, J = 7.6 Hz, 2 H),
1.68 (m, 2 H), 1.40 (m, 2 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6
Hz, 3 H).
N-{2-[5-(2-Methyl[1,3]dioxolan-2-yl)thiophen-2-yl]ben-
zyl}isobutyramide (19)
N-(2-Bromobenzyl)isobutyramide (5; 0.256 g, 1 mmol), 2-methyl-
2-thiophen-2-yl[1,3]dioxolane (0.340 g, 2 mmol), KOAc (0.196 g,
2 mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 19 in 67% yield (231 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 6.95 (d,
J = 3.4 Hz, 1 H), 6.80 (d, J = 3.4 Hz, 1 H), 6.10 (m, 1 H), 4.50 (d,
J = 5.6 Hz, 2 H), 4.02 (m, 4 H), 2.36 (sept, J = 7.6 Hz, 1 H), 1.77 (s,
3 H), 1.10 (d, J = 7.6 Hz, 6 H).
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

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Direct Heteroarylation of Bromobenzylacetamide Derivatives
2563
13C NMR (50 MHz, CDCl3): d = 176.9, 147.6, 141.1, 136.3, 133.7,
130.8, 128.8, 128.3, 127.3, 126.4, 124.4, 107.0, 64.9, 41.5, 35.3,
27.5, 19.5.
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22. Found: C, 66.47; H,
5.31.
N-{1-[4-(5-Cyanothiophen-2-yl)phenyl]ethyl}propionamide
(24)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol),
thiophene-2-carbonitrile (0.218 g, 2 mmol), KOAc (0.196 g, 2
mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 24 in 54% yield (154 mg).
1H NMR (200 MHz, CDCl3): d = 7.70–7.50 (m, 3 H), 7.35 (d,
J = 8.2 Hz, 2 H), 7.24 (d, J = 3.9 Hz, 1 H), 6.00 (m, 1 H), 5.10 (m,
1 H), 2.18 (q, J = 7.6 Hz, 2 H), 1.48 (d, J = 7.5 Hz, 3 H), 1.16 (t,
J = 7.6 Hz, 3 H).
Anal. Calcd for C19H23NO3S: C, 66.06; H, 6.71. Found: C, 65.94; H,
6.80.
N-{3-[5-(2-Methyl[1,3]dioxolan-2-yl)thiophen-2-yl]benzyl}pro-
pionamide (20)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 2-methyl-
2-thiophen-2-yl[1,3]dioxolane (0.340 g, 2 mmol), KOAc (0.196 g,
2 mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 20 in 79% yield (262 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 7.18 (d,
J = 3.4 Hz, 1 H), 7.00 (d, J = 3.4 Hz, 1 H), 5.90 (m, 1 H), 4.44 (d,
J = 5.6 Hz, 2 H), 3.98 (m, 4 H), 2.26 (q, J = 7.6 Hz, 2 H), 1.79 (s, 3
H), 1.08 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.9, 146.8, 143.4, 139.3, 134.6,
129.2, 126.8, 125.1, 125.0, 124.7, 122.9, 107.0, 64.9, 43.4, 29.6,
27.4, 9.9.
13C NMR (50 MHz, CDCl3): d = 173.5, 151.9, 145.6, 131.5, 138.4,
127.0, 126.7, 123.2, 114.8, 108.4, 48.5, 29.6, 21.8, 9.8.
Anal. Calcd for C16H16N2OS: C, 67.58; H, 5.67. Found: C, 67.60; H,
5.78.
N-[2-(5-Formyl-1-methylpyrrol-2-yl)benzyl]propionamide (25)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 1-methyl-
2-formylpyrrole (0.218 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 25
in 73% yield (197 mg).
1H NMR (200 MHz, CDCl3): d = 9.59 (s, 1 H), 7.50–7.20 (m, 4 H),
7.00 (d, J = 3.4 Hz, 1 H), 6.22 (d, J = 3.4 Hz, 1 H), 5.70 (m, 1 H),
4.29 (d, J = 5.6 Hz, 2 H), 3.70 (s, 3 H), 2.18 (q, J = 7.6 Hz, 2 H),
1.20 (t, J = 7.6 Hz, 3 H).
Anal. Calcd for C18H21NO3S: C, 65.23; H, 6.39. Found: C, 65.25; H,
6.48.
N-{1-[4-(5-Acetylthiophen-2-yl)phenyl]ethyl}propionamide
(21)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 2-
acetylthiophene (0.252 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 21
in 76% yield (229 mg).
1H NMR (200 MHz, CDCl3): d = 7.62 (d, J = 3.9 Hz, 1 H), 7.60 (d,
J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 3.9 Hz, 1 H),
6.00 (d, J = 7.1 Hz, 1 H), 5.11 (m, 1 H), 2.53 (s, 3 H), 2.18 (q,
J = 7.6 Hz, 2 H), 1.48 (d, J = 7.5 Hz, 3 H), 1.16 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 178.6, 172.5, 140.8, 137.3, 131.3,
129.8, 129.1, 128.7, 127.7, 126.4, 123.1, 110.0, 40.2, 32.7, 28.6,
8.8.
Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71. Found: C, 71.21; H,
6.58.
13C NMR (50 MHz, CDCl3): d = 190.7, 173.1, 152.5, 144.7, 142.9,
133.6, 132.2, 126.9, 126.5, 123.9, 48.3, 29.7, 26.5, 21.7, 9.8.
N-{1-[4-(5-Formyl-1-methylpyrrol-2-yl)phenyl]ethyl}propion-
amide (26)
N-[1-(4-Bromophenyl)ethyl]propionamide (3, 0.256 g, 1 mmol), 1-
methyl-2-formylpyrrole (0.218 g, 2 mmol), KOAc (0.196 g, 2
mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 26 in 70% yield (199 mg).
1H NMR (200 MHz, CDCl3): d = 9.55 (s, 1 H), 7.39 (d, J = 8.2 Hz,
2 H), 7.26 (d, J = 8.2 Hz, 2 H), 6.97 (d, J = 3.4 Hz, 1 H), 6.27 (d,
J = 3.4 Hz, 1 H), 6.10 (m, 1 H), 5.16 (m, 1 H), 3.90 (s, 3 H), 2.22 (q,
J = 7.6 Hz, 2 H), 1.50 (d, J = 7.5 Hz, 3 H), 1.15 (t, J = 7.6 Hz, 3 H).
Anal. Calcd for C17H19NO2S: C, 67.74; H, 6.35. Found: C, 67.70; H,
6.49.
N-{1-[4-(5-Propionylthiophen-2-yl)phenyl]ethyl}propion-
amide (22)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 1-
thiophen-2-ylpropan-1-one (0.280 g, 2 mmol), KOAc (0.196 g, 2
mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 22 in 79% yield (249 mg).
1H NMR (200 MHz, CDCl3): d = 7.63 (d, J = 3.9 Hz, 1 H), 7.60 (d,
J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 3.9 Hz, 1 H),
6.05 (d, J = 7.1 Hz, 1 H), 5.11 (m, 1 H), 2.87 (t, J = 7.5 Hz, 2 H),
2.18 (q, J = 7.6 Hz, 2 H), 1.48 (d, J = 7.5 Hz, 3 H), 1.16 (t, J = 7.6
Hz, 3 H), 1.07 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 179.9, 173.5, 144.6, 144.5, 133.3,
130.2, 129.8, 126.8, 125.0, 111.2, 48.8, 34.7, 30.1, 22.3, 10.3.
Anal Calcd for C17H20N2O2: C, 71.81; H, 7.09. Found: C, 72.04; H,
7.17.
13C NMR (50 MHz, CDCl3): d = 194.3, 173.5, 152.3, 145.0, 142.9,
N-[3-(5-Acetyl-1-methylpyrrol-2-yl)benzyl]propionamide (27)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 1-methyl-
2-acetylpyrrole (0.246 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 27
in 81% yield (230 mg).
133.1, 132.6, 127.3, 127.0, 124.2, 48.7, 32.6, 30.1, 22.2, 10.2, 9.1.
Anal. Calcd for C18H21NO2S: C, 68.54; H, 6.71. Found: C, 68.46; H,
6.80.
N-[2-(5-Cyanothiophen-2-yl)benzyl]propionamide (23)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), thiophene-
2-carbonitrile (0.218 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 23
in 65% yield (176 mg).
1H NMR (200 MHz, CDCl3): d = 7.70–7.30 (m, 4 H), 7.08 (d,
J = 3.4 Hz, 1 H), 5.80 (m, 1 H), 4.51 (d, J = 5.6 Hz, 2 H), 2.24 (q,
J = 7.6 Hz, 2 H), 1.15 (t, J = 7.6 Hz, 3 H).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 7.00 (d,
J = 3.4 Hz, 1 H), 6.30 (m, 1 H), 6.19 (d, J = 3.4 Hz, 1 H), 4.46 (d,
J = 5.6 Hz, 2 H), 3.83 (s, 3 H), 2.44 (s, 3 H), 2.24 (q, J = 7.6 Hz, 2
H), 1.16 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 188.6, 173.9, 142.6, 139.2, 132.0,
128.8, 128.6, 128.4, 128.2, 127.5, 116.5, 109.4, 43.5, 35.1, 29.6,
27.3, 9.9.
Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09. Found: C, 72.01; H,
6.89.
13C NMR (50 MHz, CDCl3): d = 173.6, 149.2, 137.7, 136.7, 131.3,
131.1, 129.9, 129.3, 127.9, 127.3, 114.0, 109.7, 41.6, 29.5, 9.7.
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

2564
N. Laidaoui et al.
PAPER
N-{1-[4-(5-Acetyl-1-methylpyrrol-2-yl)phenyl]ethyl}propion-
amide (28)
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 32
in 67% yield (193 mg).
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 1-
methyl-2-acetylpyrrole (0.246 g, 2 mmol), KOAc (0.196 g, 2
mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 28 in 66% yield (197 mg).
1H NMR (200 MHz, CDCl3): d = 7.39 (d, J = 8.2 Hz, 2 H), 7.26 (d,
J = 8.2 Hz, 2 H), 7.01 (d, J = 3.4 Hz, 1 H), 6.18 (d, J = 3.4 Hz, 1 H),
6.10 (m, 1 H), 5.16 (m, 1 H), 3.85 (s, 3 H), 2.45 (s, 3 H), 2.22 (q,
J = 7.6 Hz, 2 H), 1.50 (d, J = 7.5 Hz, 3 H), 1.15 (t, J = 7.6 Hz, 3 H).
1H NMR (200 MHz, CDCl3): d = 7.68 (s, 1 H), 7.50–7.20 (m, 4 H),
6.15 (m, 1 H), 4.33 (d, J = 5.6 Hz, 2 H), 3.00 (t, J = 7.6 Hz, 2 H),
2.18 (q, J = 7.6 Hz, 2 H), 1.75 (sext, J = 7.6 Hz, 2 H), 1.11 (t, J = 7.6
Hz, 3 H), 1.05 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.9, 170.8, 139.5, 138.5, 137.6,
131.9, 129.3, 127.3, 125.8, 125.5, 43.4, 35.5, 29.6, 23.3, 13.6, 9.9.
Anal. Calcd for C16H20N2OS: C, 66.63; H, 6.99. Found: C, 66.51; H,
7.17.
13C NMR (50 MHz, CDCl3): d = 188.9, 173.4, 144.2, 143.6, 132.3,
130.9, 129.9, 126.7, 120.2, 109.7, 48.7, 35.6, 30.0, 27.7, 22.2, 10.2.
N-{1-[4-(2-Propylthiazol-5-yl)phenyl]ethyl}propionamide (33)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 2-
n-propylthiazole (0.254 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 33
in 81% yield (245 mg).
1H NMR (200 MHz, CDCl3): d = 7.77 (s, 1 H), 7.47 (d, J = 8.4 Hz,
2 H), 7.32 (d, J = 8.4 Hz, 2 H), 6.10 (m, 1 H), 5.15 (m, 1 H), 2.97 (t,
J = 7.6 Hz, 2 H), 2.18 (q, J = 7.6 Hz, 2 H), 1.75 (sext, J = 7.6 Hz, 2
H), 1.40 (d, J = 7.5 Hz, 2 H), 1.11 (t, J = 7.6 Hz, 3 H), 1.05 (t,
J = 7.6 Hz, 3 H).
Anal. Calcd for C18H22N2O2: C, 72.46; H, 7.43. Found: C, 72.50; H,
7.54.
Methyl 1-Methyl-5-[2-(propionylaminomethyl)phenyl]-1H-
pyrrole-2-carboxylate (29)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), methyl 1-
methylpyrrole-2-carboxylate (278 g, 2 mmol), KOAc (0.196 g, 2
mmol), and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3
mL) gave 29 in 65% yield (195 mg).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 7.04 (d,
J = 3.4 Hz, 1 H), 6.10 (d, J = 3.4 Hz, 1 H), 5.60 (m, 1 H), 4.20 (d,
J = 5.6 Hz, 2 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 2.18 (q, J = 7.6 Hz, 2
H), 1.15 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.8, 162.2, 139.4, 138.9, 131.7,
131.6, 129.8, 129.1, 127.8, 123.2, 117.8, 109.6, 51.5, 41.7, 34.2,
29.9, 10.1.
13C NMR (50 MHz, CDCl3): d = 173.3, 170.6, 143.5, 138.0, 137.4,
130.5, 126.8, 126.7, 48.2, 35.5, 29.6, 23.3, 21.7, 13.6, 9.9.
Anal. Calcd for C17H22N2OS: C, 67.51; H, 7.33. Found: C, 67.54; H,
7.40.
N-[3-(2,3-Dimethylimidazol-4-yl)benzyl]propionamide (34)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 1,2-di-
methylimidazole (0.192 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 34
in 47% yield (121 mg).
Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71. Found: C, 67.90; H,
6.54.
N-{1-[4-(1-Methylpyrrol-2-yl)phenyl]ethyl}propionamide (30)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol), 1-
methylpyrrole (0.324 g, 4 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 30
in 73% yield (187 mg).
1H NMR (200 MHz, CDCl3): d = 7.55–7.30 (m, 4 H), 7.73 (t, J = 2.2
Hz, 1 H), 7.22–7.18 (m, 2 H), 5.70 (m, 1 H), 5.10 (m, 1 H), 3.72 (s,
3 H), 2.18 (q, J = 7.6 Hz, 2 H), 1.45 (d, J = 7.5 Hz, 2 H), 1.11 (t,
J = 7.6 Hz, 3 H).
1H NMR (200 MHz, CDCl3): d = 7.50–7.20 (m, 4 H), 6.92 (s, 1 H),
6.15 (m, 1 H), 4.42 (d, J = 5.6 Hz, 2 H), 3.50 (s, 3 H), 2.42 (s, 3 H),
2.22 (q, J = 7.6 Hz, 2 H), 1.09 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 174.8, 145.8, 139.3, 133.3, 130.3,
129.1, 127.9, 127.6, 127.3, 124.5, 43.3, 31.3, 29.6, 13.1, 9.9.
Anal. Calcd for C15H19NO3: C, 70.01; H, 7.44. Found: C, 70.14; H,
7.29.
N-[3-(3,5-Dimethylisoxazol-4-yl)benzyl]propionamide (35)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 3,5-di-
methylisoxazole (0.194 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 35
in 73% yield (188 mg).
13C NMR (50 MHz, CDCl3): d = 173.4, 142.3, 134.6, 132.7, 129.2,
126.6, 124.1, 109.1, 108.1, 48.7, 35.4, 30.2, 22.2, 10.3.
Anal. Calcd for C16H20N2O: C, 74.97; H, 7.86. Found: C, 74.91; H,
7.71.
1H NMR (200 MHz, CDCl3): d = 7.50–7.10 (m, 4 H), 6.05 (m, 1 H),
4.48 (d, J = 5.6 Hz, 2 H), 2.40 (s, 3 H), 2.25 (s, 3 H), 2.26 (q, J = 7.6
Hz, 2 H), 1.19 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.8, 165.2, 158.6, 140.8, 130.2,
129.1, 128.3, 128.1, 126.8, 116.3, 43.3, 29.6, 11.5, 10.8, 9.8.
N-[2-(2-Propylthiazol-5-yl)benzyl]propionamide (31)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), 2-n-pro-
pylthiazole (0.254 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 31
in 72% yield (208 mg).
1H NMR (200 MHz, CDCl3): d = 7.50 (s, 1 H), 7.45–7.20 (m, 4 H),
5.90 (m, 1 H), 4.42 (d, J = 5.6 Hz, 2 H), 2.95 (t, J = 7.6 Hz, 2 H),
2.18 (q, J = 7.6 Hz, 2 H), 1.80 (sext, J = 7.6 Hz, 2 H), 1.10 (t, J = 7.6
Hz, 3 H), 1.05 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.9, 172.3, 140.9, 137.1, 135.4,
131.7, 130.9, 129.6, 129.4, 128.0, 42.0, 35.8, 29.9, 23.7, 14.1, 10.2.
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02. Found: C, 69.67; H,
7.20.
N-{1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]ethyl}propion-
amide (36)
N-[1-(4-Bromophenyl)ethyl]propionamide (3 ; 0.256 g, 1 mmol),
3,5-dimethylisoxazole (0.194 g, 2 mmol), KOAc (0.196 g, 2 mmol),
and PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave
36 in 80% yield (218 mg).
Anal. Calcd for C16H20N2OS: C, 66.63; H, 6.99. Found: C, 66.84; H,
7.11.
1H NMR (200 MHz, CDCl3): d = 7.38 (d, J = 8.4 Hz, 2 H), 7.21 (d,
J = 8.4 Hz, 2 H), 5.97 (m, 1 H), 5.15 (m, 1 H), 2.39 (s, 3 H), 2.25 (s,
3 H), 2.24 (q, J = 7.6 Hz, 2 H), 1.51 (d, J = 7.5 Hz, 3 H), 1.16 (t,
J = 7.6 Hz, 3 H).
N-[3-(2-Propylthiazol-5-yl)benzyl]propionamide (32)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), 2-n-pro-
pylthiazole (0.254 g, 2 mmol), KOAc (0.196 g, 2 mmol), and
Synthesis 2010, No. 15, 2553–2566 © Thieme Stuttgart · New York

PAPER
Direct Heteroarylation of Bromobenzylacetamide Derivatives
2565
13C NMR (50 MHz, CDCl3): d = 173.0, 165.2, 158.7, 142.8, 129.4,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35.
129.3, 126.5, 116.2, 48.7, 30.1, 22.3, 11.9, 11.2, 10.2.
(e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,
1173. (f) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
(g) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(h) Ackermann, L.; Vincente, R.; Kapdi, A. R. Angew.
Chem. Int. Ed. 2009, 48, 9792. (i) Roger, J.; Gottumukkala,
A. L.; Doucet, H. ChemCatChem 2010, 2, 20.
Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40. Found: C, 70.45; H,
7.22.
N-(2-Benzooxazol-2-ylbenzyl)propionamide (37)
N-(2-Bromobenzyl)propionamide (1; 0.242 g, 1 mmol), benz-
oxazole (0.238 g, 1 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 37
in 80% yield (224 mg).
1H NMR (200 MHz, CDCl3): d = 8.20 (d, J = 6.6 Hz, 1 H), 7.85–
7.10 (m, 8 H), 4.80 (d, J = 5.6 Hz, 2 H), 2.22 (q, J = 7.6 Hz, 2H ),
1.10 (t, J = 7.6 Hz, 3 H)).
(4) For recent examples of direct arylations of furans, see:
(a) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005,
70, 7578. (b) Lindahl, K.-F.; Carroll, A.; Quinn, R. J.;
Ripper, J. A. Tetrahedron Lett. 2006, 47, 7493. (c)Beccalli,
E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Synthesis 2008, 136. (d) Gottumukkala, A. L.; Doucet, H.
Adv. Synth. Catal. 2008, 350, 2183. (e) Liégaut, B.;
Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
Chem. 2009, 74, 1826. (f) Dong, J. J.; Roger, J.; Pogan, F.;
Doucet, H. Green Chem. 2009, 11, 1832. (g) Ionita, M.;
Roger, J.; Doucet, H. ChemSusChem 2010, 3, 367.
(5) For recent examples of direct arylations of thiophenes, see:
(a) David, E.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron
2007, 63, 8999. (b) Chiong, H. A.; Daugulis, O. Org. Lett.
2007, 9, 1449. (c) Battace, A.; Lemhadri, M.; Zair, T.;
Doucet, H.; Santelli, M. Adv. Synth. Catal. 2007, 349, 2507.
(d) Amaladass, P.; Clement, J. A.; Mohanakrishnan, A. K.
Tetrahedron 2007, 63, 10363. (e) Derridj, F.;
13C NMR (50 MHz, CDCl3): d = 172.3, 161.2, 149.1, 140.8, 137.7,
131.1, 130.6, 128.6, 126.8, 124.5, 123.6, 118.9, 109.6, 41.4, 28.8,
8.6.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75. Found: C, 72.99; H,
5.87.
N-(3-Benzooxazol-2-ylbenzyl)propionamide (38)
N-(3-Bromobenzyl)propionamide (2; 0.242 g, 1 mmol), benz-
oxazole (0.238 g, 1 mmol), KOAc (0.196 g, 2 mmol) and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 38
in 78% yield (218 mg).
Gottumukkala, A. L.; Djebbar, S.; Doucet, H. Eur. J. Inorg.
Chem. 2008, 2550. (f) Nakano, M.; Tsurugi, H.; Satoh, T.;
Miura, M. Org. Lett. 2008, 10, 1851. (g) Roger, J.; Požgan,
F.; Doucet, H. Green Chem. 2009, 11, 425. (h) Dong, J. J.;
Roger, J.; Doucet, H. Tetrahedron Lett. 2009, 50, 2778.
(6) For recent examples of direct arylations of pyrroles or
indoles, see: (a) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur.
J. Org. Chem. 2006, 1379. (b) Wang, X.; Gribkov, D. V.;
Sames, D. J. Org. Chem. 2007, 72, 1476. (c) Lebrasseur,
N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (d) Fall,
Y.; Doucet, H.; Santelli, M. ChemSusChem 2009, 2, 153.
(e) Roger, J.; Doucet, H. Adv. Synth. Catal. 2009, 351, 1977.
(7) For recent examples of direct arylations of thiazoles, see:
(a) Gottumukkala, A. L.; Doucet, H. Eur. J. Inorg. Chem.
2007, 3629. (b) Campeau, L.-C.; Bertrand-Laperle, M.;
Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 3276. (c) Martin, T.; Verrier, C.;
Hoarau, C.; Marsais, F. Org. Lett. 2008, 10, 2909.
1H NMR (200 MHz, CDCl3): d = 8.18 (s, 1 H), 7.85–7.15 (m, 7 H),
6.10 (m, 1 H), 4.66 (d, J = 5.6 Hz, 2 H), 2.25 (q, J = 7.6 Hz, 2 H),
1.10 (t, J = 7.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 174.3, 163.1, 151.1, 142.3, 139.8,
131.4, 129.7, 127.8, 127.1, 127.0, 125.7, 125.1, 120.4, 111.0, 43.6,
30.1, 10.3.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75. Found: C, 72.87; H,
5.59.
N-[1-(4-Benzooxazol-2-ylphenyl)ethyl]propionamide (39)
N-[1-(4-Bromophenyl)ethyl]propionamide (3; 0.256 g, 1 mmol),
benzoxazole (0.238 g, 1 mmol), KOAc (0.196 g, 2 mmol), and
PdCl(dppb)(C3H5) (0.012 g, 0.02 mmol) in DMAC (3 mL) gave 39
in 76% yield (224 mg).
1H NMR (200 MHz, CDCl3): d = 8.22 (d, J = 8.2 Hz, 2 H), 7.80–
7.70 (m, 1 H), 7.60–7.50 (m, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.35–
7.25 (m, 2 H), 6.04 (d, J = 7.5 Hz, 1 H), 5.18 (m, 1 H), 2.20 (q,
J = 7.6 Hz, 2 H), 1.44 (d, J = 7.5 Hz, 3 H), 1.12 (t, J = 7.6 Hz, 3 H).
(d) Roger, J.; Požgan, F.; Doucet, H. J. Org. Chem. 2009, 74,
1179.
(8) For recent examples of direct arylations of imidazoles, see:
(a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel,
S. Eur. J. Org. Chem. 2006, 693. (b) Cerna, I.; Pohl, R.;
Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8, 5389.
(c) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R.
Tetrahedron 2007, 63, 1970. (d) Bellina, F.; Cauteruccio,
S.; Di Flore, A.; Rossi, R. Eur. J. Org. Chem. 2008, 5436.
(e) Bellina, F.; Cauteruccio, S.; Di Flore, A.; Marchietti, C.;
Rossi, R. Tetrahedron 2008, 64, 6060. (f)Roger, J.;Doucet,
H. Tetrahedron 2009, 65, 9772.
13C NMR (50 MHz, CDCl3): d = 173.5, 151.1, 147.6, 142.5, 128.4,
127.7, 127.1, 126.5, 125.6, 125.0, 120.4, 111.0, 48.8, 30.2, 22.1,
10.3.
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16. Found: C, 73.57; H,
6.23.
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