Palladium-catalysed direct arylation of heteroaromatics using unprotected iodoanilines with inhibition of the amination reaction

Article abstract of DOI:10.1055/s-0031-1291124

The palladium-catalysed direct arylation of heteroaromatics with unprotected iodoanilines proceeds in moderate to high yields using only 1 mol% Pd(OAc)₂ as the catalyst and potassium acetate as the base. No amination reaction was observed under these conditions. A wide variety of heteroarenes have been successfully employed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1291124

2264▌
PAPER
paper
Palladium-Catalysed Direct Arylation of Heteroaromatics Using Unprotected
Iodoanilines with Inhibition of the Amination Reaction
Direct Arylation of Heteroaromatics
Anissa Beladhria,a,b,c Kassem Beydoun,b Hamed Ben Ammar,*a Ridha Ben Salem,c Henri Doucet*b
a
Laboratoire Laboratoire de Chimie Organique Appliquée, (99 UR 12-13) Université de Gabès, Faculté des Sciences de Gabès, 6072 Gabès,
Tunisia
b
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
c
Laboratoire de Chimie Organique Physique (99 UR 12-13) Université de Sfax, Faculté des Sciences de Sfax, Route de la Soukra km 4,
3038 Sfax, Tunisia
Received: 19.03.2012; Accepted after revision: 18.04.2012
halides has proved to be a very powerful method for the
Abstract: The palladium-catalysed direct arylation of heteroaro-
synthesis of a wide variety of arylated heteroaromatics.3–7
matics with unprotected iodoanilines proceeds in moderate to high
yields using only 1 mol% Pd(OAc)2 as the catalyst and potassium
acetate as the base. No amination reaction was observed under these
conditions. A wide variety of heteroarenes have been successfully
employed.
However, the functional group tolerance of this reaction
imposes some limitations. For example, very few direct
couplings of unprotected haloanilines have been reported
so far. The palladium-catalysed reaction of anilines with
aryl halides to produce biarylamines (Buchwald–Hartwig
amination) is a well-known reaction (Scheme 1, top).8 On
the other hand, palladium-catalysed direct arylation using
unprotected haloanilines has rarely been described and, in
most cases, 2-arylations of oxazole or thiazole derivatives
have been reported.9 Concerning the palladium-catalysed
direct C-5 arylation of furans, thiophenes, pyrroles, or thi-
azoles, low yields were obtained (Scheme 1, bottom).10
For example, the 5-arylation of a furan derivative with 4-
iodoaniline provides the coupling product in only 31%
yield.10a Similarly, Koutentis and co-workers have also re-
ported the 5-arylation of an isothiazole with 4-iodo-2-ni-
troaniline in 41% yield.10b It should be noted that some
direct arylations of heteroaromatics containing unprotect-
ed NH2 substituents with aryl halides have also been re-
ported.11 Therefore, an extension to the scope of the C-5
arylation of heteroaromatics with unprotected haloani-
lines to a wider variety of heteroaromatics and aniline de-
rivatives would be beneficial. Moreover, higher yields for
the coupling of such compounds need to be obtained to
provide economically viable procedures.
Key words: catalysis, amines, heterocycles, palladium, green
chemistry
The development of methods that allow easy access to a
variety of heteroaromatics bearing an aniline substituent
is an important field of research in organic chemistry, due
to the biological properties of some of these derivatives.
For example, Tanaproget is a tissue-selective, non-steroi-
dal contraceptive progesterone receptor agonist, and Sa-
prisartan is a used in the treatment of hypertension and
heart failure (Figure 1).1
H2N
O
Br
N
N
O
NH
O
F3CO2S
CN
N
Saprisartan
S
N
Me
H
Tanaproget
Figure 1 Examples of bioactive aniline derivatives
Ar
[Pd], base
NH2
NH
+
ArX
Buchwald–Hartwig
amination
In 1990, Ohta and co-workers reported that the 2- or 5-ar-
ylation of several heteroaromatics, including furans and
thiophenes, with aryl halides proceed, in moderate to good
yields, via a C–H bond activation, using palladium cata-
lysts.2a,b Since these results were reported, the palladium-
catalysed direct arylation2c–l of heteroaromatics with aryl
NH2
NH2
Z
[Pd], base
this work
Z
X
+
H
Y
Y
X = Cl, Br, I
Y = O, S, N
Z = C, N
Scheme 1
SYNTHESIS 2012, 44, 2264–2276
Advanced online publication: 13.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291124; Art ID: SS-2012-Z0283-OP
© Georg Thieme Verlag Stuttgart · New York

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Direct Arylation of Heteroaromatics
2265
As palladium-catalysed amination reactions require spe- tion to produce biarylamines was detected. On the other
cific bases (NaOt-Bu, KOH or Cs2CO3) and catalysts (pal- hand, traces of homocoupled 4-iodoaniline were detected
ladium associated to bidentate or sterically hindered in some cases. We also examined the influence of some
phosphine ligands),8 we might expect to be able to per- bases; carbonates were found to be ineffective (Table 1,
form palladium-catalysed direct arylations of haloanilines entries 6 and 7), whereas use of sodium acetate led to a
with heteroaromatics without protection of the NH2 func- conversion that was similar to that obtained with potassi-
tion. The direct use of unprotected anilines would be use- um acetate (Table 1, entries 4 and 8). We then compared
ful in organic synthesis because it would allow the the reactivity of 4-bromoaniline and 4-iodoaniline. A
protection deprotection sequence to be avoided, and higher reactivity of 4-iodoaniline was observed (Table 1,
would provide more environmentally and economically entries 3 and 12), which is certainly due to an easier oxi-
attractive access to such arylated heteroaromatics. The dative addition of 4-iodoaniline to palladium in the pres-
major by-products of the reaction would be a base associ- ence of this catalyst. Finally, the influence of the nature of
ated with HX, instead of metallic salts produced under the solvent was examined. Reactions performed in N,N-
more classical cross-coupling procedures.
dimethylformamide (DMF) or N-methyl-2-pyrrolidinone
(NMP) were found to give 1 in lower yields, whereas the
use of cyclopentyl methyl ether (CPME), which had been
found to be a suitable solvent for the direct arylation of
several heteroaromatics with electron-poor aryl bro-
mides,4s was ineffective (Table 1, entries 13–15).
Here, we wish to report on the reaction of unprotected
haloanilines with a set of heteroaromatics using a phos-
phine-free palladium catalyst to obtain the C-5 arylated
heteroaromatics.
We initially studied the reactivity of 4-bromo- and 4-iodo-
anilines for the coupling with 2-isobutylthiazole (Scheme
2 and Table 1). The use of 1 mol% Pd(OAc)2 or [Pd-
Cl(C3H5)(dppb)] at 130 °C for the coupling with 4-iodo-
anisole led to the formation of 1 in very similar
conversions of 27 and 30% (Table 1, entries 1 and 2).
Higher reaction temperature led to better conversion of 4-
iodoanisole and to a better yield of 1 when either
Pd(OAc)2 or PdCl2 was employed as the catalysts (Table
1, entries 3 and 5). It should be noted that, under these re-
action conditions, no Buchwald–Hartwig amination reac-
N
N
S
[Pd]
+
S
solvent, base
NH2
1
X
NH2
X = I, Br
Scheme 2 Coupling of 2-isobutylthiazole with 4-bromoaniline or 4-
iodoaniline
Table 1 Arylation of 4-Bromoaniline or 4-Iodoaniline with 2-Isobutylthiazole; Influence of Reaction Conditions (Scheme 2)a
Entry
X
Solvent
Base
Catalyst (mol%)
Temp (°C)
Conv. (%)b Yield of 1 (%)
1
2
I
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
Cs2CO3
NaOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Pd(OAc)2 (1)
130
130
150
150
150
150
150
150
150
150
150
150
150
150
130
27
30
65
22
64
7
20
I
PdCl(C3H5)(dppb) (1)
Pd(OAc)2 (1)
3
I
42
4
I
PdCl(C3H5)(dppb) (1)
PdCl2 (1)
5
I
6
I
PdCl(C3H5)(dppb) (1)
PdCl(C3H5)(dppb) (1)
PdCl(C3H5)(dppb) (1)
Pd(OAc)2 (1), PPh3 (2)
PdCl(C3H5)(dppb) (2)
Pd(OAc)2 (1), dppb (1)
Pd(OAc)2 (1)
7
I
11
21
28
22
40
34
44
42
0
8
I
9
I
10
11
12
13
14
15
Br
Br
Br
I
Pd(OAc)2 (1)
I
NMP
Pd(OAc)2 (1)
I
CPME
PdCl(C3H5)(dppb) (1)
a Reaction conditions: [Pd], 4-bromoaniline or 4-iodoaniline (1 equiv), 2-isobutylthiaziole (2 equiv), base (4 equiv), 20 h.
b Determined by GC and NMR analyses.
© Georg Thieme Verlag Stuttgart · New York
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A. Beladhria et al.
PAPER
We then studied the scope of this reaction with various ployed and, in most cases, good to very high yields of cou-
heteroaromatic compounds using 1 mol% Pd(OAc)2 as pling products were obtained. 2-Alkylthiophenes or
the catalyst and KOAc as the base in dimethylacetamide thiophene-2-carbonitrile gave 6, 7 and 9 in 71–84% yield
(DMAc) at 150 °C (Scheme 2 and Table 2). Coupling of (Table 3, entries 1, 2 and 4). Couplings with 4-chloro-2-
4-iodoaniline with thiophene-2-carbonitrile gave 2 in acetylthiophene or 2-chlorothiophene were also success-
72% yield (Table 2, entry 1). 4-Chloro-2-acetylthiophene ful and gave 8 and 10 in 54 and 64% yields, respectively
reacted with both 4-bromoaniline and 4-iodoaniline, how- (Table 3, entries 3 and 5). Again, no cleavage of the C–Cl
ever, a much higher yield (79%) of 3 was obtained from bond was observed. 2-n-Butylfuran was found to be less
4-iodoaniline. It should be noted that no cleavage of the reactive, and 13 was only obtained in 31% yield due to
C–Cl bond of this thiophene derivative was observed in poor conversion of 3-iodoaniline (Table 3, entry 8). The
the course of this reaction, allowing further transforma- presence of an electron-withdrawing group at C-3 of the
tions (Table 2, entries 2 and 3). A moderate yield of 4 furan derivative allowed the yield to be increased to 56%
(54%) was obtained from 1-methylpyrrole (Table 2, entry (Table 3, entry 9). The use of four equivalents of 1-meth-
4).
ylpyrrole enabled the monoarylated pyrrole 15 to be ob-
tained in 68% yield, with only traces of diarylated pyrrole
being detected (Table 3, entry 10). A lower yield of 16
was obtained in the course of the coupling of 1-methyl-2-
acetylpyrrole due to the formation of some side-products
(Table 3, entry 11). Very high conversions of 3-iodoani-
line and good yields of 17 and 18 were obtained for the
coupling with two 2-alkylthiazoles (Table 3, entries 12
and 13). When 3,5-disubstituted isoxazole was employed,
the desired C-4 arylated isoxazole 19 was obtained in 62%
yield (Table 3, entry 14).
Z
R1
Z
NH2
R2
Y
R1
or
+
N
Y
O
1–18, 20–30, 32–45
Pd(OAc)2 (1 mol%)
DMAc, KOAc
NH2
NH2
R2
X
R2
X = I, Br
Y = O, S or NMe
Z = N or C
N
O
ortho-Substituents on the aryl halides often have a signif-
icant effect on the reactions rates and yields of most pal-
ladium-catalysed reactions because of their steric and/or
coordination properties. Indeed, 2-iodoaniline was found
to react poorly (Table 4). With most heterocycles, very
low yields of the coupling products were obtained. From
thiophene-2-carbonitrile or 4-chloro-2-acetylthiophene,
20 and 21 were isolated in only 33 and 42% yields, respec-
19 and 31
Scheme 3 Direct arylation of heteroaromatics with bromoanilines or
iodoanilines
Better results were generally obtained with 3-iodoaniline
than with 4-iodoaniline (Table 3). With this substrate, a
wide variety of heteroaromatic compounds have been em-
Table 2 Palladium-Catalysed Coupling of Heteroaromatics with 4-Bromoaniline or 4-Iodoaniline (Scheme 3)a
Entry
Heteroarene
Product
Yield (%)
72
H2N
1
S
S
CN
S
CN
2
Cl
Cl
H2N
2
3
79
O
11b
O
S
3
H2N
N
4
5
54c
42
N
Me
Me
4
N
H2N
N
S
S
5
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv), 4-iodoaniline (1 equiv), KOAc (4 equiv), DMAc, 150 °C, 20 h.
b 4-Bromoaniline (1 equiv) was used.
c 1-Methylpyrrole (4 equiv) was used.
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Direct Arylation of Heteroaromatics
2267
tively (Table 4, entries 1 and 2). We also compared the re- product 22 was obtained in 34% from 4-bromoaniline and
activity of 2-bromoaniline and 2-iodoaniline for the in 53% from iodoaniline (Table 4, entries 3 and 4).
coupling with 2-isobutylthiazole; in this case, the target
Table 3 Palladium-Catalysed Coupling of Heteroaromatics with 3-Iodoaniline (Scheme 3)a
Entry
1
Heteroarene
Product
Yield (%)
75
H2N
S
S
6
H2N
2
3
71
54
S
S
S
7
H2N
S
Cl
Cl
8
H2N
4
5
84
64
S
S
S
CN
CN
9
Cl
H2N
Cl
O
O
O
S
10
H2N
6
7
71
61
S
O
S
11
H2N
O
O
S
S
O
O
12
H2N
8
9
31
56
O
O
O
O
13
H2N
CO2Me
CO2Me
14
© Georg Thieme Verlag Stuttgart · New York
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A. Beladhria et al.
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Table 3 Palladium-Catalysed Coupling of Heteroaromatics with 3-Iodoaniline (Scheme 3)a (continued)
Entry
10
Heteroarene
Product
Yield (%)
H2N
68b
N
N
Me
Me
15
H2N
O
O
11
57
N
N
Me
Me
16
H2N
N
N
N
N
12
13
83
81
S
S
S
S
17
H2N
18
H2N
N
O
N
O
14
62
19
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv), 3-iodoaniline (1 equiv), KOAc (4 equiv), DMAc, 150 °C, 20 h.
b 1-Methylpyrrole (4 equiv) was used.
We then examined the functional group tolerance of the
reaction towards the aniline substrate for such couplings
(Table 5, Table 6, Table 7, and Table 8). Use of 4-iodoan-
iline bearing a chloro substituent at C-2 led to the forma-
tion of coupling products 23–32 in moderate to high
yields (Table 5). Under the reaction conditions, no cleav-
age of the C–Cl bond was observed, allowing further
transformations.
Table 4 Palladium-Catalysed Coupling of Heteroaromatics with 2-
Bromoaniline or 2-Iodoaniline (Scheme 3)a
Entry
Heteroarene
Product
Yield (%)
33
NH2
1
S
S
S
CN
CN
Similar results were obtained for the coupling of hetero-
aromatics with 2-fluoro-4-iodoaniline (Table 6). The best
results were obtained for the reaction with thiophene-2-
carbonitrile and 2-isobutylthiazole, which achieved yields
of 85 and 92%, respectively (Table 6, entries 1 and 4). In
the presence of methyl 2-methylfuran-3-carboxylate or
ethyl 2-methyl-thiazole-4-carboxylate, lower yields were
obtained due to partial decomposition of the reactants (Ta-
ble 6, entries 2 and 5).
20
Cl
H2N
Cl
O
2
42
O
S
21
22
NH2
N
N
3
4
53
An ester substituent at C-2 of 4-iodoaniline was also tol-
erated (Table 7). Again, the highest yields were obtained
for the coupling with thiophene-2-carbonitrile and 2-iso-
butylthiazole (Table 7, entries 1 and 5). It should be noted
that such couplings allow the formation of highly func-
tionalised compounds without protection in only one step.
S
34b
S
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv),
2-iodoaniline (1 equiv), KOAc (4 equiv), DMAc, 150 °C, 20 h.
b 2-Bromoaniline (1 equiv) was used.
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Direct Arylation of Heteroaromatics
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Table 5 Palladium-Catalysed Coupling of Heteroaromatics with
Table 6 Palladium-Catalysed Coupling of Heteroaromatics with 2-
2-Chloro-4-iodoaniline (Scheme 3)a
Fluoro-4-iodoaniline (Scheme 3)a
Entry Heteroarene
Product
Yield
(%)
Entry
Heteroarene
Product
Yield
(%)
H2N
H2N
S
S
S
1
76
80
62
1
85
61
CN
S
Cl
S
F
CN
23
33
CO2Me
H2N
CO2Me
H2N
CN
2
O
N
S
2
Cl
CN
F
O
24
34
CO2Me
CO2Me
H2N
H2N
O
N
3
3
4
65b
92
Cl
N
O
F
Me
Me
25
35
H2N
N
H2N
N
4
5
6
7
64b
53b
46
N
S
Cl
Me
Me
S
F
26
36
EtO2C
H2N
N
EtO2C
N
N
H2N
Cl
Ph
Ph
N
5
54
S
27
F
S
H2N
37
O
N
O
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv),
2-fluoro-4-iodoaniline (1 equiv), KOAc (4 equiv), DMAc, 150 °C, 20
h.
N
Cl
Me
Me
28
b 1-Methylpyrrole (4 equiv) was used.
N
H2N
N
S
90
S
Cl
For example, product 39 contains chloro, acetyl, ester and
unprotected NH2 substituents (Table 7, entry 2).
29
EtO2C
Finally, we examined the reactivity of 2-iodo-4-trifluoro-
methylaniline with heteroaromatics (Table 8). This sub-
strate was found to be more reactive than 2-iodoaniline
(Table 4). For example, the coupling of 2-isobutylthiazole
with 2-iodo-4-trifluoromethylaniline gave 45 in 83%
yield; whereas, from 2-iodoaniline 22 the yield was only
53% (compare Table 4, entry 3 and Table 8, entry 2). Use
of 2-iodo-4-trifluoromethylaniline and methyl 2-methyl-
furan-3-carboxylate led to the formation of 44 in 61%
yield (Table 8, entry 1). Again, the presence of an elec-
tron-withdrawing substituent on the aniline derivative fa-
voured the reaction. This result seems to confirm that the
rate-limiting step of the reaction is the oxidative addition
of the 2-iodoaniline to palladium.
EtO2C
N
H2N
N
8
9
66
71
53
S
S
Cl
30
N
O
H2N
N
O
Cl
31
N
O
H2N
N
10
O
Cl
Ph
In conclusion, these results demonstrate that unprotected
iodoanilines can be employed as coupling partners for pal-
ladium-catalysed direct arylation reactions. When appro-
priate reaction conditions are employed, only the direct
arylation coupling products are obtained. No formation of
amination products was detected. Moreover, this proce-
Ph
32
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv), 2-
chloro-4-iodoaniline (1 equiv), KOAc (4 equiv), DMAc, 150 °C, 20 h.
b Pyrrole derivative (4 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York
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Table 7 Palladium-Catalysed Coupling of Heteroaromatics with
Table 8 Palladium-Catalysed Coupling of Heteroaromatics with 2-
Ethyl 2-Amino-5-iodobenzoate (Scheme 3)a
Iodo-4-trifluoromethylaniline (Scheme 3)a
Entry Heteroarene
Product
Yield
(%)
Entry Heteroarene
Product
Yield
(%)
NH2
H2N
CO2Me
S
CO2Me
CN
1
77
61
60
S
EtO2C
1
61
CN
O
O
F3C
38
Cl
44
Cl
NH2
H2N
O
N
2
S
N
O
S
EtO2C
2
83
S
S
F3C
39
CO2Me
45
CO2Me
H2N
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv),
2-iodo-4-trifluoromethylaniline (1 equiv), KOAc (4 equiv), DMAc,
150 °C, 20 h.
O
N
3
EtO2C
40
O
iodoanilines or on the heteroaromatics are tolerated, al-
lowing the synthesis of highly functionalised compounds
in only one step.
H2N
4
5
64b
73
N
EtO2C
Me
Me
41
DMAc (99%) was purchased from Acros. Pd(OAc)2, PdCl2,
[Pd(C3H5)Cl]2, 1,4-bis(diphenylphosphino)butane (98%), and
KOAc (99%) were purchased from Alfa Aesar. These compounds
were not purified before use. NMR data were collected on Bruker
AC300 and Bruker Avance 400 spectrometers.
N
H2N
N
S
EtO2C
S
42
Preparation of the [PdCl(C3H5)(dppb)] Catalyst
EtO2C
An oven-dried 40 mL Schlenk tube equipped with a magnetic stir-
ring bar under an argon atmosphere was charged with
[Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol).
Anhydrous CH2Cl2 (10 mL) was added and the solution was stirred
at r.t. for 20 min. The solvent was removed in vacuum and the yel-
low powder was used without purification.
EtO2C
N
H2N
N
6
72
S
EtO2C
S
43
31P NMR (81 MHz, CDCl3): δ = 19.3 (s).
a Reaction conditions: Pd(OAc)2 (0.01 equiv), heteroarene (2 equiv),
ethyl 2-amino-5-iodobenzoate (1 equiv), KOAc (4 equiv), DMAc,
150 °C, 20 h.
Synthesis of Compounds 1–45; General Procedure
The iodoaniline derivative (1 mmol), heteroarene (2 or 4 mmol, see
Tables), KOAc (0.392 g, 4 mmol), and Pd(OAc)2 (2.2 mg, 0.01
mmol) were dissolved in DMAc (4 mL) under an argon atmosphere.
The reaction mixture was stirred at 150 °C for 20 h, then the solvent
was evaporated and the product was purified by silica gel column
chromatography.
b 1-Methylpyrrole (4 equiv) was used.
dure is economically and environmentally attractive for
several reasons: (1) with most iodoanilines the reactions
can be performed using only 1 mol% Pd(OAc)2 as the cat-
alyst, (2) there is no need to eliminate phosphine deriva-
tives at the end of the reaction, (3) it allows the protection
deprotection sequence of NH2 to be avoided, (4) the major
by-products of these couplings are AcOH/KI, instead of
the metallic salts that are generated with more classical
coupling procedures such as Suzuki, Negishi or Stille re-
actions, and (5) it reduces the number of steps required to
prepare these compounds compared to other types of cou-
plings (the method avoids the preliminary preparation of
a requisite organometallic reagent). Finally, it should be
noted that a range of functional groups, such as acetyl, es-
ter, nitrile, trifluoromethyl, chloro and fluoro either on the
4-(2-Isobutylthiazol-5-yl)phenylamine (1)
4-Iodoaniline (0.219 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2
mmol) afforded 1, which was purified by column chromatography
(pentane–Et2O, 1:1).
Yield: 0.098 g (42%); brown solid; mp 126 °C.
1H NMR (300 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.34 (d, J = 7.1 Hz,
2 H), 6.69 (d, J = 7.1 Hz, 2 H), 3.81 (br s, 2 H), 2.86 (d, J = 7.0 Hz,
2 H), 2.17–2.10 (m, 1 H), 1.03 (d, J = 7.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 168.0, 146.4, 138.9, 135.8, 127.8,
122.0, 115.3, 42.5, 29.8, 22.3.
Anal. Calcd for C13H16N2S (232.35): C, 67.20; H, 6.94. Found: C,
67.11; H, 6.99.
Synthesis 2012, 44, 2264–2276
© Georg Thieme Verlag Stuttgart · New York

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Direct Arylation of Heteroaromatics
2271
5-(4-Aminophenyl)thiophene-2-carbonitrile (2)
4-Iodoaniline (0.219 g, 1 mmol) and thiophene-2-carbonitrile
(0.218 g, 2 mmol) afforded 2, which was purified by column chro-
matography (pentane–Et2O, 1:1).
Anal. Calcd for C14H17NS (231.36): C, 72.68; H, 7.41. Found: C,
72.54; H, 7.40.
3-(5-Methylthiophen-2-yl)phenylamine (7)
3-Iodoaniline (0.219 g, 1 mmol) and 2-methylthiophene (0.196 g, 2
mmol) afforded 7, which was purified by column chromatography
(pentane–Et2O, 1:1).
Yield: 0.144 g (72%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 3.7 Hz, 1 H), 7.41 (d,
J = 8.3 Hz, 2 H), 7.11 (d, J = 3.7 Hz, 1 H), 6.71 (d, J = 8.3 Hz, 2 H),
3.93 (br s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 152.8, 147.9, 138.5, 127.7, 122.6,
121.2, 115.2, 114.9, 105.9.
Yield: 0.134 g (71%); brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.05 (t, J = 7.8 Hz, 1 H), 6.99 (d,
J = 3.3 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.80 (s,1 H), 6.64 (d, J =
3.3 Hz, 1 H), 6.50 (d, J = 7.9 Hz, 1 H), 3.61 (br s, 2 H), 2.42 (s,
3 H).
Anal. Calcd for C11H8N2S (200.26): C, 65.97; H, 4.03. Found: C,
66.08; H, 4.18.
13C NMR (75 MHz, CDCl3): δ = 146.7, 142.2, 139.2, 135.7, 129.7,
126.0, 122.8, 116.1, 114.0, 112.1, 15.4.
1-[5-(4-Aminophenyl)-4-chlorothiophen-2-yl]ethanone (3)
4-Iodoaniline (0.219 g, 1 mmol) and 4-chloro-2-acetylthiophene
(0.321 g, 2 mmol) afforded 3, which was purified by column chro-
matography (pentane–Et2O, 1:1).
Anal. Calcd for C11H11NS (189.28): C, 69.80; H, 5.86. Found: C,
69.67; H, 5.98.
3-(5-Chlorothiophen-2-yl)phenylamine (8)
Yield: 0.198 g (79%); brown solid; mp 125 °C.
1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.44 (d, J = 8.4 Hz,
2 H), 6.63 (d, J = 8.4 Hz, 2 H), 3.86 (br s, 2 H), 2.44 (s, 3 H).
3-Iodoaniline (0.219 g, 1 mmol) and 2-chlorothiophene (0.238 g, 2
mmol) afforded 8, which was purified by column chromatography
(pentane–Et2O, 1:1).
13C NMR (100 MHz, CDCl3): δ = 189.7, 147.7, 145.9, 139.1, 134.1,
Yield: 0.113 g (54%); yellow oil.
129.9, 121.2, 120.3, 114.8, 26.2.
1H NMR (400 MHz, CDCl3): δ = 7.07 (t, J = 7.8 Hz, 1 H), 6.95 (d,
J = 3.7 Hz, 1 H), 6.85 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 3.8 Hz, 1 H),
6.76 (s, 1 H), 6.56 (d, J = 7.8 Hz, 1 H), 3.86 (br s, 2 H).
Anal. Calcd for C12H10ClNOS (251.73): C, 57.25; H, 4.00. Found:
C, 57.38; H, 4.21.
13C NMR (100 MHz, CDCl3): δ = 146.9, 143.2, 134.7, 129.9, 128.8,
126.9, 122.1, 116.0, 114.7, 112.0.
4-(1-Methylpyrrol-2-yl)phenylamine (4)
4-Iodoaniline (0.219 g, 1 mmol) and 1-methylpyrrole (0.324 g, 4
mmol) afforded 4, which was purified by column chromatography
(pentane–Et2O, 3:2).
Anal. Calcd for C10H8ClNS (209.70): C, 57.28; H, 3.85. Found: C,
57.47; H, 3.74.
Yield: 0.093 g (54%); brown oil.
5-(3-Aminophenyl)thiophene-2-carbonitrile (9)
3-Iodoaniline (0.219 g, 1 mmol) and thiophene-2-carbonitrile
(0.218 g, 2 mmol) afforded 9, which was purified by column chro-
matography (pentane–Et2O, 1:1).
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.1 Hz, 2 H), 6.73 (d,
J = 8.1 Hz, 2 H), 6.69 (s, 1 H), 6.19 (s, 1 H), 6.14 (s, 1 H), 3.75 (br s,
2 H), 3.63 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.3, 134.9, 130.1, 123.8, 122.6,
Yield: 0.168 g (84%); yellow oil.
114.9, 107.5, 107.4, 34.8.
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 3.9 Hz, 1 H), 7.23 (d,
J = 3.9 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.00 (d, J = 7.8 Hz, 1 H),
6.87 (t, J = 1.8 Hz, 1 H), 6.73 (dd, J = 7.8, 1.8 Hz, 1 H), 3.65 (br s,
2 H).
13C NMR (75 MHz, CDCl3): δ = 152.3, 147.3, 138.3, 133.2, 130.2,
123.1, 116.6, 116.2, 114.6, 112.6, 107.8.
Anal. Calcd for C11H12N2 (172.23): C, 76.71; H, 7.02. Found: C,
76.50; H, 7.18.
4-(2-Propylthiazol-5-yl)phenylamine (5)
4-Iodoaniline (0.219 g, 1 mmol) and 2-n-propylthiazole (0.254 g, 2
mmol) afforded 5, which was purified by column chromatography
(pentane–Et2O, 1:1).
Anal. Calcd for C11H8N2S (200.26): C, 65.97; H, 4.03. Found: C,
66.12; H, 4.00.
Yield: 0.092 g (42%); brown oil.
1H NMR (400 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.25 (d, J = 7.1 Hz,
2 H), 6.61 (d, J = 7.1 Hz, 2 H), 3.72 (br s, 2 H), 2.88 (t, J = 7.5 Hz,
2 H), 1.76 (sext, J = 7.5 Hz, 2 H), 0.96 (t, J = 7.5 Hz, 3 H).
1-[5-(3-Aminophenyl)-4-chlorothiophen-2-yl]ethanone (10)
3-Iodoaniline (0.219 g, 1 mmol) and 4-chloro-2-acetylthiophene
(0.321 g, 2 mmol) afforded 10, which was purified by column chro-
matography (pentane–Et2O, 1:1).
13C NMR (75 MHz, CDCl3): δ = 169.5, 146.9, 139.4, 136.3, 128.3,
122.6, 115.8, 36.0, 23.8, 14.1.
Yield: 0.161 g (64%); yellow oil.
Anal. Calcd for C12H14N2S (218.32): C, 66.02; H, 6.46. Found: C,
66.15; H, 6.30.
1H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.16 (t, J = 7.8 Hz,
1 H), 7.00 (d, J = 7.8 Hz, 1 H), 6.92 (t, J = 1.8 Hz, 1 H), 6.67 (dd,
J = 7.8, 1.8 Hz, 1 H), 3.74 (br s, 2 H), 2.45 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 189.8, 146.7, 145.1, 140.5, 133.7,
132.1, 129.7, 121.6, 118.8, 115.9, 114.8, 26.2.
3-(5-Butylthiophen-2-yl)phenylamine (6)
3-Iodoaniline (0.219 g, 1 mmol) and 2-n-butylthiophene (0.280 g, 2
mmol) afforded 6, which was purified by column chromatography
(pentane–Et2O, 1:1).
Anal. Calcd for C12H10ClNOS (251.73): C, 57.25; H, 4.00. Found:
C, 57.08; H, 4.14.
Yield: 0.173 g (75%); brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.04 (t, J = 7.8 Hz, 1 H), 7.00 (d,
J = 3.3 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.80 (s,1 H), 6.64 (d, J =
3.3 Hz, 1 H), 6.49 (d, J = 7.9 Hz, 1 H), 3.60 (br s, 2 H), 2.72 (t, J =
7.6 Hz, 2 H), 1.62–1.56 (m, 2 H), 1.36–1.31 (m, 2 H), 0.87 (t, J =
7.3 Hz, 3 H).
1-[5-(3-Aminophenyl)-4-methylthiophen-2-yl]ethanone (11)
3-Iodoaniline (0.219 g, 1 mmol) and 4-methyl-2-acetylthiophene
(0.280 g, 2 mmol) afforded 11, which was purified by column chro-
matography (pentane–Et2O, 1:1).
Yield: 0.164 g (71%); yellow oil.
13C NMR (75 MHz, CDCl3): δ = 146.7, 145.4, 141.8, 135.7, 129.7,
124.8, 122.6, 116.1, 113.9, 112.1, 33.7, 29.9, 22.2, 13.8.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2264–2276

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A. Beladhria et al.
PAPER
1-[5-(3-Aminophenyl)-1-methylpyrrol-2-yl]ethanone (16)
3-Iodoaniline (0.219 g, 1 mmol) and 1-methyl-2-acetylpyrrole
(0.246 g, 2 mmol) afforded 16, which was purified by column chro-
matography (pentane–Et2O, 1:1).
1H NMR (300 MHz, CDCl3): δ = 7.42 (s, 1 H), 7.12 (t, J = 7.8 Hz,
1 H), 6.77 (d, J = 7.8 Hz, 1 H), 6.69 (s, 1 H), 6.61 (d, J = 7.8, Hz,
1 H), 3.71 (br s, 2 H), 2.44 (s, 3 H), 2.23 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 190.6, 147.4, 146.7, 140.9, 136.2,
134.6, 134.2, 129.5, 119.0, 115.2, 115.0, 26.5, 15.0.
Yield: 0.122 g (57%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.13 (t, J = 7.7 Hz, 1 H), 6.94 (d,
J = 3.9 Hz, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 6.65–6.60 (m, 2 H), 6.10
(d, J = 3.9 Hz, 1 H), 3.80 (s, 3 H), 3.71 (br s, 2 H), 2.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 188.5, 146.5, 143.3, 132.8, 131.8,
129.4, 119.7, 119.6, 115.8, 115.0, 109.1, 35.2, 27.3.
Anal. Calcd for C13H13NOS (231.31): C, 67.50; H, 5.66. Found: C,
67.59; H, 5.79.
3-[5-(2-Methyl[1,3]dioxolan-2-yl)thiophen-2-yl]phenylamine
(12)
3-Iodoaniline (0.219 g, 1 mmol) and 2-methyl-2-thiophen-2-
yl[1,3]dioxolane (0.340 g, 2 mmol) afforded 12, which was purified
by column chromatography (pentane–Et2O, 1:1).
Anal. Calcd for C13H14N2O (214.26): C, 72.87; H, 6.59. Found: C,
73.04; H, 6.67.
Yield: 0.159 g (61%); yellow solid; mp 105 °C.
3-(2-Isobutylthiazol-5-yl)phenylamine (17)
1H NMR (400 MHz, CDCl3): δ = 7.07 (t, J = 7.9 Hz, 1 H), 7.05 (d,
J = 3.5 Hz, 1 H), 6.95–9.91 (m, 2 H), 6.83 (s, 1 H), 6.54 (d, J =
7.84 Hz, 1 H), 3.93–4.03 (m, 4 H), 3.66 (br s, 2 H), 1.75 (s, 3 H).
3-Iodoaniline (0.219 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2
mmol) afforded 17, which was purified by column chromatography
(pentane–Et2O, 1:1).
13C NMR (100 MHz, CDCl3): δ = 146.8, 146.3, 144.1, 135.3, 129.8,
Yield: 0.193 g (83%); yellow oil.
124.9, 122.6, 116.3, 114.4, 112.3, 107.2, 65.0, 27.5.
1H NMR (300 MHz, CDCl3): δ = 7.70 (s, 1 H), 7.05 (t, J = 7.8 Hz,
1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.75 (s, 1 H), 6.53 (d, J = 7.6 Hz,
1 H), 3.65 (br s, 2 H), 2.78 (d, J = 7.4 Hz, 2 H), 2.07–2.02 (m, 1 H),
0.93 (d, J = 7.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 169.4, 147.0, 138.7, 137.4, 132.5,
129.9, 116.9, 114.8, 112.9, 42.5, 29.8, 22.3.
Anal. Calcd for C14H15NO2S (261.34): C, 64.34; H, 5.79. Found: C,
64.50; H, 5.64.
3-(5-Butylfuran-2-yl)phenylamine (13)
3-Iodoaniline (0.219 g, 1 mmol) and 2-n-butylfuran (0.248 g, 2
mmol) afforded 13, which was purified by column chromatography
(pentane–Et2O, 1:1).
Anal. Calcd for C13H16N2S (232.35): C, 67.20; H, 6.94. Found: C,
67.11; H, 6.78.
Yield: 0.067 g (31%); brown oil.
1H NMR (500 MHz, CDCl3): δ = 7.07 (t, J = 7.7 Hz, 1 H), 6.96 (d,
J = 7.6 Hz, 1 H), 6.92 (s, 1 H), 6.50 (d, J = 7.7 Hz, 1 H), 6.43 (d, J =
2.8 Hz, 1 H), 5.98 (d, J = 2.8 Hz, 1 H), 3.63 (br s, 2 H), 2.61 (t, J =
7.6 Hz, 2 H), 1.65–1.56 (m, 2 H), 1.40–1.30 (m, 2 H), 0.88 (t, J =
7.32 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.2, 152.2, 132.2, 129.5, 114.0,
113.7, 109.9, 106.7, 105.6, 30.2, 27.9, 22.3, 13.8.
3-(2-Propylthiazol-5-yl)phenylamine (18)
3-Iodoaniline (0.219 g, 1 mmol) and 2-n-propylthiazole (0.254 g, 2
mmol) afforded 18, which was purified by column chromatography
(pentane–Et2O, 1:1).
Yield: 0.177 g (81%); brown oil.
1H NMR (400 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.05 (t, J = 7.8 Hz,
1 H), 6.83 (d, J = 7.5 Hz, 1 H), 6.75 (s, 1 H), 6.53 (d, J = 7.5 Hz,
1 H), 3.66 (br s, 2 H), 2.87 (t, J = 7.7 Hz, 2 H), 1.76 (sext., J =
7.6 Hz, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).
Anal. Calcd for C14H17NO (215.29): C, 78.10; H, 7.96. Found: C,
78.23; H, 7.99.
13C NMR (100 MHz, CDCl3): δ = 170.4, 147.0, 138.6, 137.4, 132.6,
129.9, 117.0, 114.8, 112.9, 35.6, 23.3, 13.6.
Methyl 5-(3-Aminophenyl)-2-methylfuran-3-carboxylate (14)
3-Iodoaniline (0.219 g, 1 mmol) and methyl 2-methylfuran-3-car-
boxylate (0.280 g, 2 mmol) afforded 14, which was purified by col-
umn chromatography (pentane–Et2O, 1:1).
Anal. Calcd for C12H14N2S (218.32): C, 66.02; H, 6.46. Found: C,
66.14; H, 6.34.
Yield: 0.129 g (56%); brown oil.
3-(3,5-Dimethylisoxazol-4-yl)phenylamine (19)
3-Iodoaniline (0.219 g, 1 mmol) and 3,5-dimethylisoxazole (0.194
g, 2 mmol) afforded 19, which was purified by column chromatog-
raphy (pentane–Et2O, 1:1).
1H NMR (300 MHz, CDCl3): δ = 7.09 (t, J = 7.7 Hz, 1 H), 6.97 (d,
J = 7.7 Hz, 1 H), 6.91 (s, 1 H), 6.76 (s, 1 H), 6.54 (d, J = 7.7 Hz,
1 H), 3.78 (br s, 3 H), 2.57 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.5, 158.6, 151.9, 146.7, 131.0,
Yield: 0.117 g (62%); yellow oil.
129.7, 115.0, 114.5, 114.2, 110.1, 105.4, 51.4, 13.9.
1H NMR (300 MHz, CDCl3): δ = 7.22 (t, J = 7.8 Hz, 1 H), 6.68 (dd,
J = 8.0, 2.3 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 6.57 (t, J = 2.0 Hz,
1 H), 3.80 (br s, 2 H), 2.41 (s, 3 H), 2.28 (s, 3 H).
Anal. Calcd for C13H13NOS (231.25): C, 67.52; H, 5.67. Found: C,
67.75; H, 5.54.
13C NMR (75 MHz, CDCl3): δ = 165.1, 158.8, 146.8, 131.5, 129.7,
119.4, 116.8, 115.5, 114.2, 11.6, 10.8.
3-(1-Methylpyrrol-2-yl)phenylamine (15)
3-Iodoaniline (0.219 g, 1 mmol) and 1-methylpyrrole (0.324 g, 4
mmol) afforded 15, which was purified by column chromatography
(pentane–Et2O, 1:1).
Anal. Calcd for C11H12N2O (188.23): C, 70.19; H, 6.43. Found: C,
70.30; H, 6.51.
Yield: 0.117 g (68%); brown oil.
5-(2-Aminophenyl)thiophene-2-carbonitrile (20)
2-Iodoaniline (0.219 g, 1 mmol) and thiophene-2-carbonitrile
(0.218 g, 2 mmol) afforded 20, which was purified by column chro-
matography (pentane–Et2O, 3:2).
1H NMR (500 MHz, CDCl3): δ = 7.23 (t, J = 7.76 Hz, 1 H), 6.83 (d,
J = 7.5 Hz, 1 H), 6.76 (t, J = 2.0 Hz, 1 H), 6.73 (t, J = 2.0 Hz, 1 H),
6.66 (dd, J = 7.5, 2.0 Hz, 1 H), 6.25–6.20 (m, 2 H), 3.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.4, 134.8, 134.4, 129.2, 123.5,
Yield: 0.066 g (33%); brown oil.
119.2, 115.4, 113.7, 108.4, 107.7, 35.1.
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 3.8 Hz, 1 H), 7.20–
Anal. Calcd for C11H12N2 (172.23): C, 76.71; H, 7.02. Found: C,
76.80; H, 7.10.
7.14 (m, 3 H), 6.77–6.70 (m, 2 H), 3.91 (br s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 149.2, 144.1, 138.0, 130.8, 130.6,
125.9, 119.0, 117.6, 116.5, 114.3, 108.8.
Synthesis 2012, 44, 2264–2276
© Georg Thieme Verlag Stuttgart · New York

PAPER
Direct Arylation of Heteroaromatics
2273
Anal. Calcd for C11H8N2S (200.26): C, 65.97; H, 4.03. Found: C,
66.14; H, 4.17.
1H NMR (500 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.27 (d, J = 8.2 Hz,
1 H), 6.70 (d, J = 8.2 Hz, 1 H), 6.62 (s, 1 H), 4.08 (br s, 2 H), 3.78
(s, 3 H), 2.58 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.5, 159.0, 152.0, 143.4, 125.8,
124.3, 122.6, 120.4, 116.8, 115.9, 104.5, 52.3, 14.8.
1-[5-(2-Aminophenyl)-4-chlorothiophen-2-yl]ethanone (21)
2-Iodoaniline (0.219 g, 1 mmol) and 4-chloro-2-acetylthiophene
(0.321 g, 2 mmol) afforded 21, which was purified by column chro-
matography (pentane–Et2O, 1:1).
Anal. Calcd for C13H12ClNO3 (265.69): C, 58.77; H, 4.55. Found:
C, 58.72; H, 4.68.
Yield: 0.106 g (42%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.54 (s, 1 H), 7.20–7.17 (m, 1 H),
7.10 (d, J = 7.7 Hz, 1 H), 6.75 (t, J = 7.5 Hz, 1 H), 6.72 (d, J =
7.5 Hz, 1 H), 3.78 (br s, 2 H), 2.49 (s, 3 H).
2-Chloro-4-(1-methylpyrrol-2-yl)phenylamine (26)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 1-methylpyrrole
(0.324 g, 4 mmol) afforded 26, which was purified by column chro-
matography (pentane–Et2O, 7:3).
13C NMR (100 MHz, CDCl3): δ = 189.7, 144.8, 142.4, 142.3, 132.8,
131.6, 131.0, 124.2, 118.3, 116.0, 115.7, 26.4.
Yield: 0.132 g (64%); brown oil.
Anal. Calcd for C12H10ClNOS (251.73): C, 57.25; H, 4.00. Found:
C, 57.36; H, 3.89.
1H NMR (500 MHz, CDCl3): δ = 7.30 (d, J = 2.1 Hz, 1 H), 7.10 (dd,
J = 8.3, 1.9 Hz, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 6.67 (t, J = 2.3 Hz,
1 H), 6.17 (t, J = 2.9 Hz, 1 H), 6.13 (dd, J = 3.5, 1.7 Hz, 1 H), 4.09
(br s, 2 H), 3.62 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 141.9, 133.7, 129.7, 128.4, 124.7,
123.2, 119.2, 115.7, 108.2, 107.7, 34.9.
2-(2-Isobutylthiazol-5-yl)phenylamine (22)
2-Iodoaniline (0.219 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2
mmol) afforded 22, which was purified by column chromatography
(pentane–Et2O, 1:1).
Anal. Calcd for C11H11ClN2 (206.67): C, 63.93; H, 5.36. Found: C,
63.80; H, 5.28.
Yield: 0.123 g (53%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.64 (s, 1 H), 7.16 (d, J = 7.6 Hz,
1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.75–6.67 (m, 2 H), 3.88 (br s, 2 H),
2.86 (d, J = 7.0 Hz, 2 H), 2.18–2.10 (m, 1 H), 0.97 (d, J = 7.6 Hz,
6 H).
2-Chloro-4-(1-phenylpyrrol-2-yl)phenylamine (27)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 1-phenylpyrrole
(0.572 g, 4 mmol) afforded 27, which was purified by column chro-
matography (pentane–Et2O, 4:1).
13C NMR (125 MHz, CDCl3): δ = 170.4, 144.2, 140.1, 134.8, 131.2,
129.5, 118.7, 116.7, 116.0, 42.5, 29.8, 22.4.
Yield: 0.142 g (53%); brown oil.
Anal. Calcd for C13H16N2S (232.35): C, 67.20; H, 6.94. Found: C,
67.25; H, 6.84.
1H NMR (500 MHz, CDCl3): δ = 7.30–7.20 (m, 3 H), 7.10 (d, J =
7.8 Hz, 2 H), 7.02 (s, 1 H), 6.81 (s, 1 H), 6.66 (d, J = 8.3 Hz, 1 H),
6.49 (d, J = 8.3 Hz, 1 H), 6.25 (m, 2 H), 3.90 (br s, 2 H).
4-(5-Butylthiophen-2-yl)-2-chlorophenylamine (23)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 2-n-butylthiophene
(0.280 g, 2 mmol) afforded 23, which was purified by column chro-
matography (pentane–Et2O, 4:1).
13C NMR (125 MHz, CDCl3): δ = 140.4, 139.5, 131.9, 128.3, 128.1,
127.0, 125.7, 124.8, 123.5, 122.8, 118.0, 114.5, 108.9, 108.2.
Anal. Calcd for C16H13ClN2 (268.74): C, 71.51; H, 4.88. Found: C,
71.41; H, 4.89.
Yield: 0.202 g (76%); brown oil.
1H NMR (400 MHz, CDCl3): δ = 7.38 (m, 1 H), 7.25–7.15 (m, 1 H),
7.00–6.90 (m, 1 H), 6.80–6.65 (m, 2 H), 4.05 (br s, 2 H), 2.79 (t, J =
7.6 Hz, 2 H), 1.70–1.60 (m, 2 H), 1.45–1.35 (m, 2 H), 0.94 (t, J =
7.32 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 146.6, 144.5, 141.8, 140.7, 126.4,
125.0, 124.8, 121.4, 119.5, 115.9, 33.7, 29.8, 22.1, 13.8.
1-[5-(4-Amino-3-chlorophenyl)-1-methylpyrrol-2-yl]ethanone
(28)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 1-methyl-2-acetyl-
pyrrole (0.246 g, 2 mmol) afforded 28, which was purified by col-
umn chromatography (pentane–Et2O, 3:2).
Yield: 0.115 g (46%); green oil.
1H NMR (500 MHz, CDCl3): δ = 7.24 (s, 1 H), 7.03 (d, J = 8.2 Hz,
1 H), 6.94 (d, J = 3.9 Hz, 1 H), 6.75 (d, J = 8.2 Hz, 1 H), 6.08 (d, J =
3.9 Hz, 1 H), 4.16 (br s, 2 H), 3.80 (s, 3 H), 2.40 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 188.5, 143.2, 142.2, 131.8, 130.4,
128.9, 122.5, 119.9, 115.6, 109.0, 35.3, 27.4.
Anal. Calcd for C14H16ClNS (265.80): C, 63.26; H, 6.07. Found: C,
63.14; H, 6.00.
5-(4-Amino-3-chlorophenyl)thiophene-2-carbonitrile (24)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and thiophene-2-carboni-
trile (0.218 g, 2 mmol) afforded 24, which was purified by column
chromatography (pentane–Et2O, 3:2).
Anal. Calcd for C13H13ClN2O (248.71): C, 62.78; H, 5.27. Found:
C, 62.70; H, 5.19.
Yield: 0.187 g (80%); yellow solid; mp 136 °C.
1H NMR (500 MHz, CDCl3): δ = 7.47 (d, J = 3.8 Hz, 1 H), 7.44 (s,
1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.04 (d, J = 3.8 Hz, 1 H), 6.72 (d, J =
8.3 Hz, 1 H), 4.24 (br s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 151.1, 144.0, 138.4, 127.4, 126.0,
123.3, 121.8, 119.5, 115.8, 114.5, 106.7.
2-Chloro-4-(2-isobutylthiazol-5-yl)phenylamine (29)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 2-isobutylthiazole
(0.282 g, 2 mmol) afforded 29, which was purified by column chro-
matography (pentane–Et2O, 7:3).
Yield: 0.239 g (90%); brown oil.
1H NMR (400 MHz, CDCl3): δ = 7.60 (s, 1 H), 7.36 (s, 1 H), 7.16
(d, J = 8.3 Hz, 1 H), 6.69 (d, J = 8.3 Hz, 1 H), 4.11 (br s, 2 H), 2.78
(d, J = 7.12 Hz, 2 H), 2.10–2.01 (m, 1 H), 0.94 (d, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.6, 142.8, 137.7, 136.4, 127.5,
126.1, 122.7, 119.5, 115.9, 42.5, 29.8, 22.3.
Anal. Calcd for C11H7ClN2S (234.71): C, 56.29; H, 3.01. Found: C,
56.21; H, 3.17.
Methyl 5-(4-Amino-3-chlorophenyl)-2-methylfuran-3-carbox-
ylate (25)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and methyl 2-methylfu-
ran-3-carboxylate (0.280 g, 2 mmol) afforded 25, which was puri-
fied by column chromatography (pentane–Et2O, 3:2).
Anal. Calcd for C13H15ClN2S (266.79): C, 58.53; H, 5.67. Found: C,
58.64; H, 5.64.
Yield: 0.164 g (62%); orange solid; mp 139 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2264–2276

2274
A. Beladhria et al.
PAPER
Ethyl 5-(4-Amino-3-chlorophenyl)-2-methylthiazole-4-carbox-
ylate (30)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and ethyl 2-methylthia-
zole-4-carboxylate (0.342 g, 2 mmol) afforded 30, which was puri-
fied by column chromatography (pentane–Et2O, 3:7).
13C NMR (100 MHz, CDCl3): δ = 164.8, 158.3, 151.7 (d, J =
238.5 Hz), 151.6 (d, J = 2.4 Hz), 134.5 (d, J = 13.5 Hz), 121.6 (d,
J = 7.2 Hz), 120.4 (d, J = 3.2 Hz), 117.2 (d, J = 4.0 Hz), 115.3,
111.3 (d, J = 20.7 Hz), 103.9, 51.6, 14.1.
Anal. Calcd for C13H12FNO3 (249.24): C, 62.65; H, 4.85. Found: C,
62.78; H, 4.94.
Yield: 0.197 g (66%); brown solid; mp 139 °C.
1H NMR (500 MHz, CDCl3): δ = 7.32 (s, 1 H), 7.12 (d, J = 8.3 Hz,
1 H), 6.67 (d, J = 8.3 Hz, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 4.25 (br s,
2 H), 2.64 (s, 3 H), 1.20 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 163.7, 162.1, 145.7, 143.8, 139.3,
130.8, 129.5, 120.6, 118.4, 114.9, 61.2, 19.2, 14.2.
2-Fluoro-4-(1-methylpyrrol-2-yl)phenylamine (35)
2-Fluoro-4-iodoaniline (0.237 g, 1 mmol) and 1-methylpyrrole
(0.324 g, 4 mmol) afforded 35, which was purified by column chro-
matography (pentane–Et2O, 3:2).
Yield: 0.124 g (65%); brown oil.
Anal. Calcd for C13H13ClN2O2S (296.77): C, 52.61; H, 4.42. Found:
C, 52.71; H, 4.49.
1H NMR (300 MHz, CDCl3): δ = 6.98 (d, J = 12.0 Hz, 1 H), 6.92 (d,
J = 8.1 Hz, 1 H), 6.75 (t, J = 8.1 Hz, 1 H), 6.62 (s, 1 H), 6.12 (s,
1 H), 6.09 (s, 1 H), 3.71 (br s, 2 H), 3.57 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.2 (d, J = 238.7 Hz), 133.8,
133.1 (d, J = 13.1 Hz), 124.9 (d, J = 2.8 Hz), 124.2 (d, J = 7.1 Hz),
123.0, 116.6 (d, J = 4.2 Hz), 115.6 (d, J = 19.2 Hz), 108.0, 107.5,
34.8.
2-Chloro-4-(3,5-dimethylisoxazol-4-yl)phenylamine (31)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 3,5-dimethylisoxa-
zole (0.194 g, 2 mmol) afforded 31, which was purified by column
chromatography (pentane–Et2O, 3:2).
Yield: 0.158 g (71%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.12 (d, J = 1.9 Hz, 1 H), 6.92 (dd,
J = 8.2, 1.9 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 4.15 (br s, 2 H), 2.35
(s, 3 H), 2.22 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.9, 158.8, 142.4, 129.9, 128.5,
121.0, 119.3, 115.9, 115.7, 11.5, 10.7.
Anal. Calcd for C11H11FN2 (190.22): C, 69.46; H, 5.83. Found: C,
69.57; H, 5.91.
2-Fluoro-4-(2-isobutylthiazol-5-yl)phenylamine (36)
2-Fluoro-4-iodoaniline (0.237 g, 1 mmol) and 2-isobutylthiazole
(0.282 g, 2 mmol) afforded 36, which was purified by column chro-
matography (pentane–Et2O, 3:2).
Anal. Calcd for C11H11ClN2O (222.67): C, 59.33; H, 4.98. Found:
C, 59.24; H, 5.06.
Yield: 0.230 g (92%); yellow solid; mp 92 °C.
1H NMR (300 MHz, CDCl3): δ = 7.61 (s, 1 H), 7.12–7.03 (m, 2 H),
6.68 (t, J = 8.2 Hz, 1 H), 3.81 (br s, 2 H), 2.77 (d, J = 7.2 Hz, 2 H),
2.08–2.02 (m, 1 H), 0.93 (d, J = 7.5 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 168.6, 151.5 (d, J = 240.0 Hz),
137.9 (d, J = 2.7 Hz), 136.4, 134.4 (d, J = 13.2 Hz), 122.9, 122.3 (d,
J = 7.1 Hz), 116.9 (d, J = 3.8 Hz), 113.5 (d, J = 20.3 Hz), 42.5, 29.8,
22.2.
2-Chloro-4-(3-methyl-5-phenylisoxazol-4-yl)phenylamine (32)
2-Chloro-4-iodoaniline (0.254 g, 1 mmol) and 3-methyl-5-phenyl-
isoxazole (0.318 g, 2 mmol) afforded 32, which was purified by col-
umn chromatography (pentane–Et2O, 1:1).
Yield: 0.151 g (53%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.50 (d, J = 7.4 Hz, 2 H), 7.27 (m,
3 H), 7.13 (s, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.75 (d, J = 8.2 Hz,
1 H), 4.18 (br s, 2 H), 2.17 (s, 3 H).
Anal. Calcd for C13H15FN2S (250.34): C, 62.37; H, 6.04. Found: C,
62.39; H, 6.17.
13C NMR (125 MHz, CDCl3): δ = 164.1, 160.2, 142.8, 130.4, 129.6,
129.2, 128.6, 127.8, 126.7, 120.8, 119.4, 116.1, 115.0, 10.5.
Ethyl 5-(4-Amino-3-fluorophenyl)-2-methylthiazole-4-carbox-
ylate (37)
2-Fluoro-4-iodoaniline (0.237 g, 1 mmol) and ethyl 2-methylthia-
zole-4-carboxylate (0.342 g, 2 mmol) afforded 37, which was puri-
fied by column chromatography (pentane–Et2O, 3:7).
Anal. Calcd for C16H13ClN2O (284.74): C, 67.49; H, 4.60. Found:
C, 67.34; H, 4.47.
5-(4-Amino-3-fluorophenyl)thiophene-2-carbonitrile (33)
2-Fluoro-4-iodoaniline (0.237 g, 1 mmol) and thiophene-2-carboni-
trile (0.218 g, 2 mmol) afforded 33, which was purified by column
chromatography (pentane–Et2O, 7:3).
Yield: 0.151 g (54%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 11.9 Hz, 1 H), 6.99 (d,
J = 8.1 Hz, 1 H), 6.69 (t, J = 8.4 Hz, 1 H), 4.25 (q, J = 7.0 Hz, 2 H),
3.86 (br s, 2 H), 2.64 (s, 3 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.6, 162.0, 150.5 (d, J =
238.8 Hz), 145.9, 139.2, 135.5 (d, J = 13.2 Hz), 126.3 (d, J =
2.9 Hz), 120.0 (d, J = 8.1 Hz), 117.0 (d, J = 20.5 Hz), 115.8 (d, J =
4.4 Hz), 61.1, 19.1, 14.1.
Yield: 0.185 g (85%); yellow solid; mp 154 °C.
1H NMR (400 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.22 (d, J = 12.0 Hz,
1 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.09 (s, 1 H), 6.78 (t, J = 8.2 Hz,
1 H), 3.96 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 151.4, 151.3 (d, J = 240.8 Hz),
138.4, 136.0 (d, J = 12.7 Hz), 122.8 (m), 121.9, 116.8 (d, J =
4.0 Hz), 114.6, 113.3 (d, J = 20.7 Hz), 106.7.
Anal. Calcd for C13H13FN2O2S (280.32): C, 55.70; H, 4.67. Found:
C, 55.61; H, 4.54.
Anal. Calcd for C11H7FN2S (218.25): C, 60.53; H, 3.23. Found: C,
60.64; H, 3.30.
Ethyl 2-Amino-5-(5-cyanothiophen-2-yl)benzoate (38)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol) and thiophene-2-
carbonitrile (0.218 g, 2 mmol) afforded 38, which was purified by
column chromatography (pentane–Et2O, 7:3).
Methyl 5-(4-Amino-3-fluorophenyl)-2-methylfuran-3-carbox-
ylate (34)
2-Fluoro-4-iodoaniline (0.237 g, 1 mmol) and methyl 2-methylfu-
ran-3-carboxylate (0.280 g, 2 mmol) afforded 34, which was puri-
fied by column chromatography (pentane–Et2O, 3:2).
Yield: 0.210 g (77%); yellow solid; mp 173 °C.
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.54 (d, J = 3.8 Hz,
1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 3.8 Hz, 1 H), 6.69 (d, J =
8.4 Hz, 1 H), 6.00 (br s, 2 H), 4.37 (q, J = 7.0 Hz, 2 H), 1.41 (t, J =
7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.5, 152.0, 151.1, 138.4, 131.8,
129.4, 121.5, 120.6, 117.4, 114.7, 111.0, 106.2, 60.8, 14.2.
Yield: 0.152 g (61%); brown solid; mp 87 °C.
1H NMR (300 MHz, CDCl3): δ = 7.21 (m, 1 H), 7.16 (d, J = 8.2 Hz,
1 H), 6.72 (t, J = 8.4 Hz, 1 H), 6.62 (s, 1 H), 3.78 (s, 3 H), 3.75 (br s,
2 H), 2.56 (s, 3 H).
Synthesis 2012, 44, 2264–2276
© Georg Thieme Verlag Stuttgart · New York

PAPER
Direct Arylation of Heteroaromatics
2275
Anal. Calcd for C14H12N2O2S (272.32): C, 61.75; H, 4.44. Found: C,
61.87; H, 4.60.
Ethyl 5-(4-Amino-3-ethoxycarbonylphenyl)-2-methylthiazole-
4-carboxylate (43)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol) and ethyl 2-
methylthiazole-4-carboxylate (0.342 g, 2 mmol) afforded 43, which
was purified by column chromatography (pentane–Et2O, 2:3).
Ethyl 5-(5-Acetyl-3-chlorothiophen-2-yl)-2-aminobenzoate (39)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol) and 4-chloro-2-
acetylthiophene (0.321 g, 2 mmol) afforded 39, which was purified
by column chromatography (pentane–Et2O, 7:3).
Yield: 0.241 g (72%); yellow solid; mp 127 °C.
1H NMR (500 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.32 (d, J = 8.5 Hz,
1 H), 6.59 (d, J = 8.54 Hz, 1 H), 5.91 (br s, 2 H), 4.27–4.21 (m,
4 H), 2.64 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.20 (t, J = 7.0 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 167.4, 163.0, 161.9, 150.7, 146.3,
138.9, 135.2, 132.6, 117.6, 116.0, 110.0, 60.9, 60.3, 19.0, 14.1,
13.9.
Yield: 0.197 g (61%); yellow solid; mp 170 °C.
1H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1 H), 7.62 (d, J = 8.4 Hz,
1 H), 7.52 (s, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 6.02 (br s, 2 H), 4.34
(q, J = 7.0 Hz, 2 H), 2.52 (s, 3 H), 1.38 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 189.6, 167.6, 151.0, 145.0, 139.3,
133.9, 133.8, 131.9, 120.6, 119.1, 116.8, 110.8, 60.7, 26.2, 14.3.
Anal. Calcd for C15H14ClNO3S (323.80): C, 55.64; H, 4.36. Found:
C, 55.75; H, 4.21.
Anal. Calcd for C16H18N2O4S (334.39): C, 57.47; H, 5.43. Found: C,
57.29; H, 5.60.
Methyl 5-(4-Amino-3-ethoxycarbonylphenyl)-2-methylfuran-3-
carboxylate (40)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol) and methyl 2-
methylfuran-3-carboxylate (0.280 g, 2 mmol) afforded 40, which
was purified by column chromatography (pentane–Et2O, 4:1).
Methyl 5-(2-Amino-5-trifluoromethylphenyl)-2-methylfuran-3-
carboxylate (44)
2-Iodo-4-trifluoromethylaniline (0.287 g, 1 mmol) and methyl 2-
methylfuran-3-carboxylate (0.280 g, 2 mmol) afforded 44, which
was purified by column chromatography (pentane–Et2O, 7:3).
Yield: 0.182 g (60%); yellow solid; mp 132 °C.
Yield: 0.182 g (61%); white solid; mp 116 °C.
1H NMR (300 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.46 (d, J = 8.4 Hz,
1 H), 6.62 (s, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 5.78 (br s, 2 H), 4.30
(q, J = 7.0 Hz, 2 H), 3.77 (s, 3 H), 2.56 (s, 3 H), 1.36 (t, J = 7.0 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 167.9, 164.7, 157.8, 151.7, 149.9,
129.7, 126.6, 118.9, 117.1, 114.9, 111.0, 103.0, 60.6, 51.4, 14.4,
13.9.
1H NMR (300 MHz, CDCl3): δ = 7.64 (s, 1 H), 7.27 (d, J = 8.4 Hz,
1 H), 6.80 (s, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 4.62 (br s, 2 H), 3.80
(s, 3 H), 2.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.2, 158.5, 149.4, 145.8, 125.8
(q, J = 3.8 Hz), 124.8 (q, J = 3.8 Hz), 124.4 (q, J = 270.6 Hz), 120.3
(q, J = 32.9 Hz), 116.2, 114.9, 114.6, 107.9, 51.5, 13.8.
Anal. Calcd for C14H12F3NO3 (299.25): C, 56.19; H, 4.04. Found: C,
56.11; H, 4.09.
Anal. Calcd for C16H17NO5 (303.31): C, 63.36; H, 5.65. Found: C,
63.47; H, 5.79.
2-(2-Isobutylthiazol-5-yl)-4-trifluoromethylphenylamine (45)
2-Iodo-4-trifluoromethylaniline (0.287 g, 1 mmol) and 2-isobutyl-
thiazole (0.282 g, 2 mmol) afforded 45, which was purified by col-
umn chromatography (pentane–Et2O, 2:3).
Ethyl 2-Amino-5-(1-methylpyrrol-2-yl)benzoate (41)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol), 1-methylpyrrole
(0.324 g, 4 mmol) afforded 41, which was purified by column chro-
matography (pentane–Et2O, 4:1).
Yield: 0.249 g (83%); brown oil.
Yield: 0.156 g (64%); green oil.
1H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 7.38 (s, 1 H), 7.32
(d, J = 8.4 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 4.23 (br s, 2 H), 2.84
(d, J = 7.2 Hz, 2 H), 2.12–2.05 (m, 1 H), 0.97 (d, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 171.1, 147.2, 140.6, 133.1, 128.4
(q, J = 3.9 Hz), 126.5 (q, J = 3.9 Hz), 120.2 (q, J = 32.9 Hz), 124.4
(q, J = 271.1 Hz), 115.9, 115.2, 42.4, 29.7, 22.3.
1H NMR (500 MHz, CDCl3): δ = 7.87 (s, 1 H), 7.24 (d, J = 8.4 Hz,
1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.13 (s, 1 H), 6.10 (s,
1 H), 5.73 (br s, 2 H), 4.28 (q, J = 7.0 Hz, 2 H), 3.55 (s, 3 H), 1.32
(t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.0, 149.4, 134.7, 134.1, 131.6,
122.7, 121.5, 116.6, 110.8, 107.7, 107.4, 60.4, 34.7, 14.3.
Anal. Calcd for C14H15F3N2S (300.34): C, 55.99; H, 5.03. Found: C,
56.14; H, 5.21.
Anal. Calcd for C14H16N2O2 (244.29): C, 68.83; H, 6.60. Found: C,
68.94; H, 6.71.
Ethyl 2-Amino-5-(2-isobutylthiazol-5-yl)-benzoate (42)
Ethyl 2-amino-5-iodobenzoate (0.291 g, 1 mmol) and 2-isobutylthi-
azole (0.282 g, 2 mmol) afforded 42, which was purified by column
chromatography (pentane–Et2O, 1:1).
Acknowledgment
We thank CNRS and ‘Rennes Metropole’ for providing financial
support.
Yield: 0.222 g (73%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.69 (d, J = 2.4 Hz,
1 H), 7.43 (d, J = 8.4 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 5.87 (br s,
2 H), 4.38 (q, J = 7.2 Hz, 2 H), 2.86 (d, J = 7.0 Hz, 2 H), 2.17–2.10
(m, 1 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.01 (d, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.9, 168.4, 150.8, 139.0, 136.8,
132.9, 130.0, 120.6, 117.9, 111.7, 61.3, 43.2, 30.5, 23.0, 15.1.
References
(1) Lednicer, D. Bicyclic Fused Heterocycles, In The Organic
Chemistry of Drug Synthesis; Vol. 7; John Wiley & Sons:
Hoboken, 2007.
(2) (a) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A.; Kurihara,
T.; Shimizu, M. Heterocycles 1985, 23, 2327. (b) Ohta, A.;
Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31,
1951. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (d) Satoh, T.; Miura, M. Chem. Lett. 2007,
36, 200. (e) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007, 40, 35. (f) Seregin, I. V.;
Anal. Calcd for C16H20N2O2S (304.41): C, 63.13; H, 6.62. Found: C,
63.18; H, 6.78.
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (g) Li, B.-J.;
© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2012, 44, 2264–2276
© Georg Thieme Verlag Stuttgart · New York