One-pot synthesis of furo- or thienoquinolines through sequential imination and intramolecular palladium-catalyzed direct arylation

Article abstract of DOI:10.1002/ejoc.201201142

The sequential imination and intramolecular palladium-catalyzed direct arylation of thiophene-3-carbaldehyde or furan-3-carbaldehyde with 2-haloanilines provided a one-pot access to furo- or thienoquinolines in high yields with H₂O and HBr as the major waste. Both electron-withdrawing and -donating substituents on the 2-haloaniline derivatives were tolerated. These furo- or thienoquinoline derivatives can be employed in the direct arylation at C-5 of the furyl or thienyl moiety, and a variety of corresponding arylation products were obtained in high yields. The sequential imination and intramolecular palladium-catalyzed direct arylation of thiophene-3-carbaldehyde or furan-3-carbaldehyde with 2-haloanilines provided a one-pot access to furo- or thienoquinolines in high yields with H₂O and HBr as the major waste. Copyright

Full text of DOI:10.1002/ejoc.201201142

FULL PAPER
DOI: 10.1002/ejoc.201201142
One-Pot Synthesis of Furo- or Thienoquinolines through Sequential Imination
and Intramolecular Palladium-Catalyzed Direct Arylation
Kassem Beydoun[a] and Henri Doucet*[a]
Keywords: Synthetic methods / Heterocycles / Fused-ring systems / Homogeneous catalysis / Palladium / P ligands / C–H
functionalization
The sequential imination and intramolecular palladium-cata- -donating substituents on the 2-haloaniline derivatives were
lyzed direct arylation of thiophene-3-carbaldehyde or furan-
3-carbaldehyde with 2-haloanilines provided a one-pot ac-
cess to furo- or thienoquinolines in high yields with H2O and
HBr as the major waste. Both electron-withdrawing and
tolerated. These furo- or thienoquinoline derivatives can be
employed in the direct arylation at C-5 of the furyl or thienyl
moiety, and a variety of corresponding arylation products
were obtained in high yields.
Introduction
Because of their biological activities, the preparation of
fused heterocyclic compounds is of considerable interest in
organic synthesis. For example, thieno-, furo-, or pyr-
rolo[3,2-c]quinolines are reported to present important
pharmacological properties (see Figure 1).[1]
Figure 2. Structure of aniline-substituted thienoquinolines used as
pharmaceutical precursors.
multistep procedure. First, thienolactam intermediates were
prepared by the cross-coupling reaction of 2-bromothio-
phene-3-carboxylate with the corresponding aniline boronic
acid. The reaction with phosphorus oxychloride (POCl3) af-
forded the corresponding chlorothienoquinoline deriva-
tives.[1d] In 1989, Yang and co-workers described the syn-
thesis of a thienoquinoline derivative through the condensa-
tion/coupling reaction of (3-carboxaldehydethiophene-2-yl)
boronic acid with N-acetyl-2-bromoaniline. Low yields were
obtained for these reactions, and the protection of the 2-
bromoaniline was crucial for the reaction to take place.[2a]
In 2007, Lemaire and co-workers described a new approach
to aryl-substituted benzothienoquinolines. After the prepa-
ration of the aniline-substituted benzothiophene, the ad-
dition of substituted benzaldehydes followed by refluxing
triflic acid resulted in the corresponding arylated benzothi-
enoquinolines through a Pictet–Spengler cyclization.[2d]
Although a number of useful synthetic protocols are
available for the preparation of furo- and thienoquinolines,
there remain many limitations such as the need of multistep
reactions and the limited scope of substrates. Therefore, de-
veloping simpler, more general, and convenient processes
using readily accessible building blocks for the synthesis of
such motifs is highly desirable (see Scheme 1).
Figure 1. General structure of thieno-, furo-, and pyrrolo[3,2-c]-
quinolines.
Related compounds have been prepared for antileukemic
evaluations[1b] and antibacterial activity studies.[1c] Some
thienoquinolines can also act as inhibitors for the protein
kinases in cancer cells (see Figure 2).[1d]
For the past two decades, thieno[3,2-c]quinoline deriva-
tives have received considerable attention in medicinal and
material chemistry. Therefore, significant efforts are di-
rected towards the discovery of more effective synthetic
methods for the preparation of molecules containing this
motif.[2] For example, Pierre and co-workers described the
syntheses of aminothienoquinoline derivatives using a
[a] UMR-CNRS 6226, Equipe “Catalyse et Organométalliques”,
Université de Rennes I,
Campus de Beaulieu, 35042 Rennes, France
Fax: +33-2-23236384
E-mail: henri.doucet@univ-rennes1.fr
Homepage: http://scienceschimiques.univ-rennes1.fr/catalyse/
personnels/interface/HD.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201142.
Eur. J. Org. Chem. 2012, 6745–6751
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6745

K. Beydoun, H. Doucet
FULL PAPER
ture was found to give the desired thienoquinoline 1c with
5% selectivity (see Table 1, Entry 7). Then, we explored the
activity of PdCl(C3H5)(dppb), as we recently demonstrated
it was one of the best catalysts for the direct arylation of
some furans, thiophenes, or thiazoles.[7b] Using 4 mol-% of
this catalyst precursor, the desired intramolecular arylation
product 1c was obtained with 20% selectivity (see Table 1,
Entry 9).
Scheme 1. Green and atom-economic synthetic method for furo-
or thienoquinoline derivatives.
To avoid the deleterious influence of a free amino group
in the reaction mixture of the catalytic intramolecular aryl-
ation, an alternative synthetic route was applied (see
Scheme 3). This method consisted of the complete in situ
preparation of N-(2-bromophenyl)thiophene imine 1a (see
Table 2, Reaction 1) followed by the Pd-catalyzed intramo-
lecular arylation to obtain quinoline derivative 1c (see
Table 3, Reaction 2).
We now report a one-pot synthesis of such quinoline de-
rivatives starting from 2-haloanilines and furan- or thio-
phene-3-carbaldehyde through the successive formation of
the corresponding imine followed by a palladium-catalyzed
intramolecular C–H bond functionalization.[3–8]
Results and Discussion
First, we examined the influence of different conditions
previously applied to a direct arylation reaction.[7] We tried
to achieve a one-pot concerted imination/arylation reaction
of thiophene-3-carbaldehyde and 2-bromoaniline to pre-
pare thienoquinoline 1c (see Scheme 2 and Table 1).
Scheme 3. One-pot sequential imination and intramolecular aryl-
ation of thiophene-3-carbaldehyde with 2-bromoaniline.
Even though xylene and toluene are typical solvents for
an imination reaction, we studied the influence of using
DMAc, which is generally employed in Pd-catalyzed aryla-
tions (see Table 2). Using 4 equiv. of thiophene-3-carboxal-
dehyde in DMAc afforded 1a in 98% yield. However, a
smaller excess amount of thiophene-3-carbaldehyde and a
more concentrated solution afforded 1a in 84–95% yield
(see Table 2, Entries 1–4). Use of toluene in the presence of
Scheme 2. Direct condensation/arylation of thiophene-3-carbal-
dehyde with 2-bromoaniline.
In the presence of 2 mol-% Pd(OAc)2 as the catalyst, molecular sieves (4 Å) at 130 °C afforded 1a in 99% yield,
KOAc as the base, and DMAc (N,N-dimethylacetamide) as whereas xylene with molecular sieves afforded 1a in 98%
the solvent at 150 °C, imination product 1a was obtained in yield (see Table 2, Entries 7 and 11). Finally, we observed
moderate yield, and no target 1c was detected. The major that 1.2 equiv. of thiophene-3-carbaldehyde afforded full
byproduct was 1d with 32% selectivity (see Table 1, En- conversion to 1a (see Table 2, Entry 9). Compound 1a cer-
try 1). No changes were detected when K2CO3 was used as tainly has the E configuration, however, these compounds
the base. Higher loadings of the base or the aldehyde had can isomerize to the reactive Z isomers.[9]
no impact on the formation of desired product. On the
Then, N-(2-bromophenyl)thiophene imine 1a prepared in
other hand, the addition of the phosphane ligand dppb situ from the addition of 2-bromoaniline to thiophene-3-
[1,4-bis(diphenylphosphanyl)butane] to the reaction mix- carbaldehyde (see Scheme 3, Reaction 1) in toluene or xy-
Table 1. Influence of the reaction conditions on palladium-catalyzed coupling of thiophene-3-carbaldehyde with 2-bromoaniline (see
Scheme 2).[a]
Entry
Pd catalyst [mol-%]
RCHO/RЈNH2
Base
1a/1b/1c/1d
Conv. [%]
1
2
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2/dppb (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (4)
2:1
2:1
4:1
4:1
4:1
4:1
4:1
4:1
1.2:1
KOAc
K2CO3
KOAc
KOAc
K2CO3
K2CO3
KOAc
KOAc
KOAc
68:0:0:32
70:0:0:30
73:0;0:27
77:0:0:23
71:0:0:29
76:0:0:24
75:0:5:20
68:0:9:23
55:0:20:25
65
60
70
83
72
80
71
75
78
3
4[b]
5
6[b]
7[b]
8[b]
9[b]
[a] Reagents and conditions: 2-bromoaniline (0.5 mmol), thiophene-3-carbaldehyde (0.6–2 mmol), Pd catalyst (2–4 mol-%), base (1 mmol),
DMAc, 150 °C, 24 h, under argon, conversion of 2-bromoaniline. [b] Base (2 mmol).
6746
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6745–6751

One-Pot Synthesis of Furo- or Thienoquinolines
Table 2. In situ preparation of N-(2-bromophenyl)thiophene imine in Reactions 1 and 2 gave a better result than using DMAc,
1a (see Scheme 3, Reaction 1).[a]
forming the desired thienoquinoline 1c in 47% yield (see
Table 3, Entries 1–4). Similar to the experiments presented
in the Table 1, different bases were employed in combina-
tion with PdCl(C3H5)(dppb) and xylene to optimize the
other reaction conditions. It was found that CsOAc led to
a better yield of 1c in 81% (see Table 3, Entries 5–8). It is
known that palladium-catalyzed C–H activation/C–C
bond-forming reactions using aryl halides as substrates are
very sensitive to the structure of the catalyst and its li-
gand.[4] Therefore, we investigated the effect on the reaction
of using Pd(OAc)2 with various ligands (see Table 3, En-
tries 9–17). PPh3 or PCy3 (Cy = cyclohexyl) formed a suit-
able combination with Pd(OAc)2 in this coupling reaction,
and the best yields of 1c were obtained in 90% yield using
xylene (see Table 3, Entry 13) and in 95 and 91% yield
using toluene (see Table 3, Entries 15 and 16, respectively).
The use of a ligand-free palladium catalyst Pd(OAc)2 did
not result in the formation of the desired intramolecular
arylation product 1c (see Table 3, Entry 18).
Entry Solvent [mL]
RCHO/RЈNH2 % Yield 1a
1
2
3
4
5
6
7
8
DMAc (1)
DMAc (1)
DMAc (0.5)
DMAc (0.5)
CPME[b] (0.5)
toluene (0.5)
toluene (1)
xylene (0.5)
xylene (0.5)
xylene (0.5)
xylene (1)
2:1
4:1
70
98
1.2:1
1.05:1
4:1
4:1
1.2:1
2:1
1.2:1
1.05:1
1.2:1
1.05:1
4:1
95
84
95[c]
52
99[c,d]
99
9
99[c]
92
10
11
12
13
98[c,d]
60[e]
87
xylene (0.5)
neat
[a] Reagents and conditions: 2-bromoaniline (0.5 mmol), thio-
phene-3-carbaldehyde (0.525–2 mmol), 150 °C, 24 h, under argon,
GC yields. [b] CPME = cyclopentyl methyl ether. [c] 130 °C.
[d] Molecular sieves (MS, 4 Å, 200 mg). [e] Room temperature.
Table 3. Palladium-catalyzed in situ intramolecular arylation of N-
(2-bromophenyl)thiophene imine 1a (see Scheme 3, Reaction 2).[a]
The scope of the one-pot sequential imination and cycli-
zation reactions of thiophene-3-carbaldehyde or furan-3-
carbaldehyde with various 2-haloanilines was then investi-
gated using Pd(OAc)2 as the catalyst, PPh3 as the ligand,
CsOAc as the base, and either xylene or toluene as the sol-
vents (see Scheme 4 and Table 4).
Yield
of 1c
[%]
Entry Palladium catalyst/L Base
[mol-%]
Solvent
[mL]
T [°C] Time
[h]
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(2)
PdCl(C3H5)(dppb)
(5)
PdCl(C3H5)(dppb)
(2)
1
2
3
4
5
6
7
8
K2CO3 DMAc (1)
150
150
130
150
150
150
150
150
48
48
48
18
18
18
18
18
14
15
30
47
2
KOAc
KOAc
KOAc
KF
DMAc (1)
CPME (1)
xylene (1)
xylene (1)
NaOAc xylene (1)
2
KOPiv
CsOAc
xylene (1)
50[b]
81
xylene (2)
xylene (1)
Scheme 4. Syntheses of furo and thienoquinoline derivatives.
9
Pd(OAc)2/2 PPh3 (5) KOAc
130
130
130
150
18
18
22
18
50
85
65
10
11
12
Pd(OAc)2/2 PPh3 (5) Cs2CO3 xylene (1)
Pd(OAc)2/2 PPh3 (2) CsOAc
Pd(OAc)2/2 PPh3 (2) CsOAc
xylene (2)
xylene (2)
71
First, we studied the reactivity of thiophene-3-carbal-
dehyde with different substituted 2-haloanilines. In the pres-
ence of electron-deficient 2-bromo-4,6-difluoroaniline,
product 2 was obtained in 78% yield, when using xylene as
the solvent (see Table 4, Entry 3) and in 90% yield when
using toluene (see Table 4, Entry 4). Similar yields of prod-
uct 3 were obtained in the presence of the 2-iodo-4-trifluor-
omethylaniline in either xylene or toluene (see Table 4, En-
tries 5 and 6). Lower yields of product 4 were obtained in
82% and 70% with 2-bromo-4-methylaniline (see Table 4,
Entries 7 and 8, respectively). A lower reactivity with 3-
acetylthiophene with 2-bromoaniline was observed, proba-
bly because of a more difficult imination reaction. In the
best case, product 5 was obtained in 55% yield (see Table 4,
Entry 9).
90[b]
(80)
61
13
14
15
Pd(OAc)2/2 PPh3 (2) CsOAc
xylene (2)
xylene (2)
toluene (2)
toluene (2)
130
130
130
18
22
24
Pd(OAc)2/dppb (2)
CsOAc
95[b,c]
(85)
91[b,c]
78[b,c]
0
Pd(OAc)2/2 PPh3 (2) CsOAc
16
17
18
Pd(OAc)2/2 PCy3 (2) CsOAc
Pd(OAc)2/2 PCy3 (2) Cs2CO3 toluene (2)
Pd(OAc)2 (2) CsOAc xylene (2)
130
130
130
24
20
18
[a] Reagents and conditions of Reaction 1: 2-bromoaniline
(0.5 mmol), thiophene-3-carbaldehyde (0.6 mmol), xylene (0.5 mL),
130 °C, 24 h, under argon. [b] MS (4 Å, 200 mg) were added.
[c] Followed by Reaction 2 in toluene, reagents and conditions: ad-
dition of palladium catalyst/L, base (2 equiv.), solvent (1 or 2 mL).
Isolated yields are in parentheses.
lene was subjected to a palladium-catalyzed intramolecular
direct arylation reaction (see Scheme 3 and Table 3). After
Then, we investigated the reactivity of furan-3-carbal-
an initial screening of various solvents and employing 1 or dehyde with 2-bromoanilines.[10] The use of 2-bromoaniline
2 mol-% of PdCl(C3H5)(dppb), we found that using xylene in xylene afforded product 6 in 70% yield (see Table 4, En-
Eur. J. Org. Chem. 2012, 6745–6751
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6747

K. Beydoun, H. Doucet
FULL PAPER
Table 4. Preparation of furo- and thienoquinoline derivatives
through a one-pot sequential imination and intramolecular aryl-
ation (see Scheme 4).[a]
Scheme 5. Palladium-catalyzed direct arylation of thieno- or furo-
quinoline derivatives.
Conclusions
[a] Reagents and conditions of Reaction 1: 2-haloaniline
(0.5 mmol), thiophene-3-carboxaldehyde (0.6 mmol), MS (4 Å.
200 mg), 130 °C, 24 h, under argon, xylene (1 mL). Followed by
Reaction 2, reagents and conditions: addition of Pd(OAc)2/2 PPh3
(2 mol-%), CsOAc (1 mmol), xylene (1 mL), 130 °C. [b] Toluene in-
stead of xylene (1 mL). [c] Pd(OAc)2/2 PPh3 (4 mol-%).
In summary, we demonstrated that when the appropriate
reaction conditions were employed, the palladium-catalyzed
intramolecular direct arylation of in situ prepared N-(2-
haloaryl)thiophene imine or N-(2-haloaryl)furan imine de-
rivatives proceeded regioselectively, starting from a variety
of 2-haloaniline derivatives and thiophene-3-carbaldehyde
or furan-3-carbaldehyde. This method provided a variety of
furo- and thienoquinoline derivatives with the formation of
water and HBr as the main byproducts. These furo- and
thienoquinoline derivatives were then employed in the di-
rect arylation at C-5 of the thienyl or furyl moiety, and a
variety of corresponding arylation products were obtained
in high yields.
try 10); whereas, the use of 2-bromo-4,6-difluoroaniline af-
forded product 7 in 89% yield (see Table 4, Entry 12). Sim-
ilar results were obtained when using 4-trifluoromethyl-2-
iodoaniline and 2-bromo-4-methylaniline to afford products
8 (see Table 4, Entries 13 and 14) and 9 (see Table 4, En-
tries 15 and 16), respectively.
We then studied the reactivity of some of the prepared
thieno- and furoquinoline derivatives in an intermolecular
palladium-catalyzed direct arylation at C-5 of the thienyl or
furyl moiety. For this, we employed the conditions de-
scribed in our previous work for the direct arylation of fur-
ans and thiophenes with different aryl bromides.[10b] We ob-
served that by using 1 mol-% Pd(OAc)2 as the catalyst, the
5-arylated thieno- or furoquinolines 10–22 were obtained
with high to very high isolated yields (see Scheme 5). Sim-
ilar reactivities were observed for the thieno- and furoquin-
olines with a minor influence from the presence of methyl,
fluoro, and trifluoromethyl substituents on the quinoline
derivative.
Experimental Section
General Methods: All reactions were performed under argon in
Schlenk tubes. Distilled toluene was used, and analytical grade xy-
lene was not distilled prior to use. Cesium acetate (99+% purity)
was used, and commercially available bromoanilines, thiophene-3-
carbaldehyde, furan-3-carbaldehyde, and aryl bromides were used
without purification. 1H (500 MHz, 25 °C) and 13C (125 MHz,
25 °C) NMR spectroscopic data were recorded using CDCl3 solu-
tions. Chemical shifts are reported in ppm relative to CDCl3 (1H
NMR, 7.29; 13C NMR, 77.0). Flash chromatography was per-
6748
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6745–6751

One-Pot Synthesis of Furo- or Thienoquinolines
formed with silica gel (230–400 mesh), using pentane/ethyl ether or
ethyl ether/methanol.
8.5 Hz, 1 H), 7.70 (t, J = 8.5 Hz, 1 H), 7.63 (d, J = 5.4 Hz, 1 H),
7.61–7.54 (m, 2 H), 3.00 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 154.7, 145.0, 143.8, 133.3, 129.4, 128.4, 126.2, 125.8,
123.7, 123.5, 123.3, 23.6 ppm. C12H9NS (199.27): calcd. C 72.33,
H 4.55; found C 72.47, H 4.41.
General Procedure for the Preparation of Thienoquinolines and Furo-
quinolines 1c and 2–9: As a typical experiment, 2-bromoaniline
(0.086 g, 0.5 mmol) and thiophene-3-carbaldehyde (0.067 g,
0.6 mmol) were stirred in a Schlenk tube containing activated mo-
lecular sieves (4 Å, 200 mg). Toluene or xylene (1 mL) was added,
and the reaction mixture was stirred under argon at room tempera-
ture or 130 °C until the full conversion to the aldimine was
achieved. The addition of Pd(OAc)2 (2.2 mg, 0.01 mmol), PPh3
(5.2 mg, 0.02 mmol), CsOAc (0.191 g, 1 mmol), and toluene or xy-
lene (1 mL) at 130 °C over 18–48 h under argon followed by evapo-
ration of the toluene and filtration of the residue through silica
gel (pentane/ether) afforded the corresponding thienoquinoline or
furoquinoline products 1c and 2–9.
Furo[3,2-c]quinoline (6): The reaction of 2-bromoaniline (0.086 g,
0.5 mmol) with furan-3-carbaldehyde (0.058 g, 0.6 mmol) over acti-
vated molecular sieves (4 Å, 0.2 g) in xylene (1 mL) afforded 6
(70%, 0.060 g) as a yellow oil. 1H NMR (500 MHz, CDCl3): δ =
9.02 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H),
7.58–7.53 (m, 2 H), 7.45 (t, J = 7.5 Hz, 1 H), 6.75 (d, J = 2.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 155.3, 145.6, 145.4,
144.7, 129.6, 128.0, 126.7, 119.9, 119.8, 117.1, 105.9 ppm.
C11H7NO (169.18): calcd. C 78.09, H 4.17; found C 78.19, H 4.37.
6,8-Difluorofuro[3,2-c]quinoline (7): The reaction of 2-bromo-4,6-
difluoroaniline (0.104 g, 0.5 mmol) with furan-3-carbaldehyde
(0.058 g, 0.6 mmol) over activated molecular sieves (4 Å, 0.2 g) in
xylene (1 mL) afforded 7 (89%, 0.091 g) as a light brown solid; m.p.
Thieno[3,2-c]quinoline (1c):[2a] The reaction of 2-bromoaniline
(0.086 g, 0.5 mmol) with thiophene-3-carbaldehyde (0.067 g,
0.6 mmol) over activated molecular sieves (4 Å, 0.2 g) in xylene
1
1
(1 mL) afforded 1c (80%, 0.074 g). H NMR (500 MHz, CDCl3):
148 °C. H NMR (500 MHz, CDCl3): δ = 9.12 (s, 1 H), 7.81 (d, J
δ = 9.30 (s, 1 H), 8.24 (d, J = 8.2 Hz, 1 H), 8.14 (d, J = 8.2 Hz, 1
H), 7.73 (t, J = 8.2 Hz, 1 H), 7.66 (t, J = 8.2 Hz, 1 H), 7.60 (d, J
= 5.3 Hz, 1 H), 7.58 (d, J = 5.3 Hz, 1 H) ppm. 13C NMR
= 2.1 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.18 (t, J = 8.8 Hz, 1 H),
7.0 (d, J = 2.1 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
160.9 (dd, J = 249.0 and 11.8 Hz), 160.1 (dd, J = 261.0 and
(125 MHz, CDCl3): δ = 146.6, 145.0, 143.8, 133.7, 130.3, 128.4, 13.3 Hz), 154.7, (t, J = 5.4 Hz), 145.9, 144.8, 132.8 (dd, J = 11.6
127.1, 126.3, 124.3, 124.0, 123.4 ppm.
and 2.0 Hz), 121.5, 118.6 (dd, J = 12.1 and 3.7 Hz), 106.3, 103.9
(dd, J = 29.0 and 23.1 Hz), 100.0 (dd, J = 23.5 and 4.9 Hz) ppm.
C11H5F2NO (205.16): calcd. C 64.40, H 2.46; found C 64.51, H
2.28.
6,8-Difluorothieno[3,2-c]quinoline (2): The reaction of 2-bromo-4,6-
difluoroaniline (0.104 g, 0.5 mmol) with thiophene-3-carbaldehyde
(0.067 g, 0.6 mmol) over activated molecular sieves (4 Å, 0.2 g) in
toluene (1 mL) afforded 2 (90%, 0.099 g) as a yellow solid; m.p.
214 °C. H NMR (500 MHz, CDCl3): δ = 9.27 (s, 1 H), 7.67 (d, J (trifluoromethyl)aniline (0.144 g, 0.5 mmol) with furan-3-carbal-
= 5.3 Hz, 1 H), 7.63 (d, J = 5.3 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 dehyde (0.058 g, 0.6 mmol) over activated molecular sieves (4 Å,
8-Trifluoromethylfuro[3,2-c]quinoline (8): The reaction of 2-iodo-4-
1
H), 7.23 (t, J = 8.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 161.1 (dd, J = 250.0 and 12.1 Hz), 160.5 (dd, J = 260.0 and
13.5 Hz), 145.9, 143.9 (m), 134.8, 131.0 (dd, J = 11.3 and 2.0 Hz),
127.9, 125.9 (dd, J = 11.8 and 3.4 Hz), 124.3, 104.0 (dd, J = 28.7
and 23.3 Hz), 103.3 (dd, J = 22.9 and 4.8 Hz) ppm. C11H5F2NS
(221.23): calcd. C 59.72, H 2.28; found C 59.71, H 2.33.
0.2 g) in xylene (1 mL) afforded 8 (70%, 0.083 g) as a brown solid;
m.p. 100 °C. H NMR (500 MHz, CDCl3): δ = 9.23 (s, 1 H), 8.54
1
(s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.82
(d, J = 2.0 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 155.5, 147.6, 146.4, 145.7, 130.8, 128.5 (q,
J = 32.8 Hz), 125.1 (q, J = 272.3 Hz), 123.9 (q, J = 3.7 Hz), 121.0,
118.1 (q, J = 4.4 Hz), 116.4, 106.3 ppm. C12H6F3NO (237.18):
calcd. C 60.77, H 2.55; found C 60.84, H 2.67.
8-(Trifluoromethyl)thieno[3,2-c]quinoline (3): The reaction of 2-
iodo-4-(trifluoromethyl)aniline (0.144 g, 0.5 mmol) with thiophene-
3-carbaldehyde (0.067 g, 0.6 mmol) over activated molecular sieves
(4 Å, 0.2 g) in xylene (1 mL) afforded 3 (93%, 0.118 g) as a brown
solid; m.p. 130 °C. 1H NMR (500 MHz, CDCl3): δ = 9.39 (s, 1 H),
8.43 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 1 H),
8-Methylfuro[3,2-c]quinoline (9): The reaction of 2-bromo-4-meth-
ylaniline (0.093 g, 0.5 mmol) with furan-3-carboxaldehyde (0.058 g,
0.6 mmol) over activated molecular sieves (4 Å, 0.2 g) in xylene
(1 mL) afforded 9 (72%, 0.066 g) as a yellow oil. 1H NMR
7.69 (d, J = 5.3 Hz, 1 H), 7.66 (d, J = 5.3 Hz, 1 H) ppm. 13C NMR (500 MHz, CDCl3): δ = 9.13 (s, 1 H), 8.12 (d, J = 8.6 Hz, 1 H),
(125 MHz, CDCl3): δ = 148.5, 145.3, 145.0, 134.5, 131.4, 129.0 (q,
8.07 (s, 1 H), 7.79 (d, J = 2.1 Hz, 1 H), 7.55 (d, J = 8.6 Hz, 1 H),
J = 32.8 Hz), 127.5, 125.3 (q, J = 272.5 Hz), 124.2 (q, J = 3.2 Hz), 6.99 (d, J = 2.1 Hz, 1 H), 2.62 (s, 3 H) ppm. 13C NMR (125 MHz,
124.1, 123.7, 121.2 (q, J = 4.3 Hz) ppm. C13H6F3NS (253.24):
calcd. C 56.91, H 2.39; found C 56.99, H 2.20.
CDCl3): δ = 155.3, 144.8, 144.6, 144.3, 137.0, 130.4, 129.4, 120.1,
118.9, 117.2, 106.1, 21.8 ppm. C12H9NO (183.21): calcd. C 78.67,
H 4.95; found C 78.79, H 4.99.
8-Methylthieno[3,2-c]quinoline (4): The reaction of 2-bromo-4-
methylaniline (0.093 g, 0.5 mmol) with thiophene-3-carbaldehyde
General Procedure for the Arylation of Furoquinolines and Thieno-
(0.067 g, 0.6 mmol) over activated molecular sieves (4 Å, 0.2 g) in quinolines: As a typical experiment, the reaction mixture of the aryl
xylene (1 mL) afforded 4 (82%, 0.081 g) as a yellow solid; m.p. bromide (0.5 mmol), the furo- or thienoquinoline derivative
96 °C. 1H NMR (500 MHz, CDCl3): δ = 9.18 (s, 1 H), 8.09 (d, J =
(1 mmol), and KOAc (0.098 g, 1 mmol) in DMAc (2 mL) in the
presence of Pd(OAc)2 (1.1 mg, 0.005 mmol) was heated at 130 °C
8.5 Hz, 1 H), 7.80 (s, 1 H), 7.51–7.45 (m, 3 H), 2.54 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 145.5, 144.3, 142.1, 137.0, 133.6, over 15–20 h under argon. Extraction with dichloromethane, evap-
130.3, 129.8, 126.0, 124.1, 123.8, 122.4, 21.5 ppm. C12H9NS
(199.27): calcd. C 72.33, H 4.55; found C 72.25, H 4.64.
oration of the solvent, and filtration of the residue through silica
gel (pentane/diethyl ether or diethyl ether/methanol) afforded the
corresponding arylation products 10–22.
4-Methylthieno[3,2-c]quinoline (5): The reaction of 2-bromoaniline
(0.086 g, 0.5 mmol) with 3-acetylthiophene (0.076 g, 0.6 mmol)
over activated molecular sieves (4 Å, 0.2 g) in xylene (1 mL) af-
(4-Thieno[3,2-c]quinolin-2-yl)benzonitrile (10): The reaction of 4-
bromobenzonitrile (0.091 g, 0.5 mmol) and 1c (0.185 g, 1 mmol)
over 18 h afforded 10 (80%, 0.114 g) as a yellow solid; m.p. 228 °C.
1H NMR (500 MHz, CDCl3): δ = 9.27 (s, 1 H), 8.24 (d, J = 8.3 Hz,
1
forded 5 (55%, 0.055 g) as a brown solid; m.p. 128 °C. H NMR
(500 MHz, CDCl3): δ = 8.16 (d, J = 8.5 Hz, 1 H), 8.09 (d, J =
Eur. J. Org. Chem. 2012, 6745–6751
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6749

K. Beydoun, H. Doucet
FULL PAPER
1 H), 8.11 (d, J = 8.3 Hz, 1 H), 7.87–7.83 (m, 3 H), 7.78–7.73 (m, (0.253 g, 1 mmol) over 20 h afforded 16 (80%, 0.142 g) as a brown
3 H), 7.76 (t, J = 8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 146.5, 145.2, 144.0, 142.4, 137.8, 134.5, 132.9, 130.5, 129.1,
127.6, 126.8, 123.8, 123.3, 121.4, 118.5, 112.0 ppm. C18H10N2S
(286.35): calcd. C 75.50, H 3.52; found C 75.32, H 3.35.
solid; m.p. 218 °C. 1H NMR (500 MHz, CDCl3): δ = 9.33 (s, 1 H),
8.36 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 8.03 (s, 1 H), 7.96 (d, J =
7.8 Hz, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.82 (s, 1 H), 7.71 (d, J =
7.8 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 148.4, 145.2, 145.0, 143.2, 135.2, 134.4, 132.1, 131.6,
130.6, 130.2, 129.8, 129.2 (q, J = 32.7 Hz), 124.6 (q, J = 3.2 Hz),
123.1, 122.8 (q, J = 272.5 Hz), 121.0 (q, J = 4.4 Hz), 120.6, 118.1,
113.8 ppm. C19H9F3N2S (354.35): calcd. C 64.40, H 2.56; found C
64.62, H 2.74.
2-(4-Nitrophenyl)thieno[3,2-c]quinoline (11): The reaction of 4-bro-
monitrobenzene (0.101 g, 0.5 mmol) and 1c (0.185 g, 1 mmol) over
15 h afforded 11 (90%, 0.138 g) as a bright yellow solid; m.p.
1
215 °C. H NMR (500 MHz, CDCl3): δ = 9.27 (s, 1 H), 8.32 (d, J
= 8.3 Hz, 2 H), 8.23 (d, J = 7.8 Hz, 1 H), 8.10 (d, J = 7.8 Hz, 1
H), 7.91–7.86 (m, 3 H), 7.76 (t, J = 7.8 Hz, 1 H), 7.66 (t, J =
7.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.5, 146.6,
145.4, 144.1, 141.8, 139.6, 134.5, 130.5, 129.2, 127.6, 126.9, 124.6,
123.8, 123.3, 122.0 ppm. C17H10N2O2S (306.34): calcd. C 66.65, H
3.29; found C 66.48, H 3.38.
3-(8-Methylthieno[3,2-c]quinolin-2-yl)benzonitrile (17): The reaction
of 3-bromobenzonitrile (0.091 g, 0.5 mmol) and 4 (0.199 g, 1 mmol)
over 20 h afforded 17 (88%, 0.132 g) as a brown solid; m.p. 192 °C.
1H NMR (500 MHz, CDCl3): δ = 9.16 (s, 1 H), 8.09 (d, J = 8.5 Hz,
1 H), 7.98 (s, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.73 (s,
1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.55 (d,
J = 8.5 Hz, 1 H), 2.61 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 145.6, 144.2, 142.4, 141.7, 137.7, 134.9, 134.5, 131.6, 131.0,
130.4, 130.1, 130.0, 129.7, 123.7, 122.4, 120.7, 118.2, 113.5,
21.5 ppm. C19H12N2S (300.38): calcd. C 75.97, H 4.03; found C
76.14, H 3.79.
(3-Thieno[3,2-c]quinolin-2-yl)benzonitrile (12): The reaction of 3-
bromobenzonitrile (0.091 g, 0.5 mmol) and 1c (0.185 g, 1 mmol)
over 20 h afforded 12 (88%, 0.126 g) as a yellow solid; m.p. 220 °C.
1H NMR (500 MHz, CDCl3): δ = 9.24 (s, 1 H), 8.22 (d, J = 8.0 Hz,
1 H), 8.07 (d, J = 8.0 Hz, 1 H), 8.00 (s, 1 H), 7.94 (d, J = 7.2 Hz,
1 H), 7.77–7.71 (m, 2 H), 7.68–7.62 (m, 2 H), 7.58 (t, J = 7.2 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 146.5, 144.8, 144.0,
141.9, 134.8, 133.5, 131.7, 130.5, 130.4, 130.0, 129.8, 128.9, 127.5,
123.8, 123.3, 120.7, 118.2, 113.6 ppm. C18H10N2S (286.35): calcd.
C 75.50, H 3.52; found C 75.67, H 3.59.
2-(Pyrimidin-5-yl)thieno[3,2-c]quinoline (18): The reaction of 5-bro-
mopyrimidine (0.080 g, 0.5 mmol) and 1c (0.185 g, 1 mmol) over
20 h afforded 18 (80%, 0.105 g) as a light brown solid; m.p. 162 °C.
1H NMR (500 MHz, CDCl3): δ = 9.31 (s, 1 H), 9.26 (s, 1 H), 9.14
(s, 2 H), 8.25 (d, J = 8.3 Hz, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 7.90
(s, 1 H), 7.78 (t, J = 8.3 Hz, 1 H), 7.69 (t, J = 7.9 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 158.2, 154.1, 146.5, 145.4, 144.1,
136.7, 134.4, 130.5, 129.2, 128.1, 127.7, 123.8, 123.4, 121.7 ppm.
C15H9N3S (263.32): calcd. C 68.42, H 3.45; found C 68.54, H 3.31.
2-(3-Nitrophenyl)thieno[3,2-c]quinoline (13): The reaction of 3-bro-
monitrobenzene (0.101 g, 0.5 mmol) and 1c (0.185 g, 1 mmol) over
20 h afforded 13 (80%, 0.122 g) as a dark bright yellow solid; m.p.
1
195 °C. H NMR (500 MHz, CDCl3): δ = 9.23 (s, 1 H), 8.54 (t, J
= 1.9 Hz, 1 H), 8.20 (d, J = 8.3 Hz, 2 H), 8.05 (d, J = 8.1 Hz, 1
H), 8.00 (d, J = 8.1 Hz, 1 H), 7.81 (s, 1 H), 7.72 (t, J = 8.1 Hz, 1
H), 7.65–7.60 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
148.8, 146.5, 144.8, 144.0, 141.7, 135.1, 134.4, 131.9, 130.4, 130.2,
128.9, 127.5, 123.7, 123.2, 123.0, 121.1, 120.0 ppm. C17H10N2O2S
(306.34): calcd. C 66.65, H 3.29; found C 66.49, H 3.17.
2-(Isoquinolin-4-yl)thieno[3,2-c]quinoline (19): The reaction of 4-
bromoisoquinoline (0.104 g, 0.5 mmol) and 1c (0.185 g, 1 mmol)
over 20 h afforded 19 (95%, 0.148 g) as a light brown solid; m.p.
1
167 °C. H NMR (500 MHz, CDCl3): δ = 9.34 (s, 1 H), 9.33 (s, 1
H), 8.76 (s, 1 H), 8.31 (d, J = 8.5 Hz, 1 H), 8.28 (d, J = 8.1 Hz, 1
H), 8.15 (d, J = 8.5 Hz, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 7.81 (t, J
= 8.1 Hz, 1 H), 7.78–7.73 (m, 2 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.66
(t, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 153.4,
146.5, 145.6, 144.1, 143.8, 138.9, 134.2, 134.1, 131.5, 130.4, 128.7,
128.4, 128.2, 127.8, 127.4, 125.4, 124.6, 124.2, 123.9, 123.4 ppm.
C20H12N2S (312.39): calcd. C 76.90, H 3.87; found C 68.68, H 3.69.
3-(6,8-Difluorothieno[3,2-c]quinolin-2-yl)benzonitrile (14): The reac-
tion of 3-bromobenzonitrile (0.091 g, 0.5 mmol) and 2 (0.110 g,
0.5 mmol) over 20 h afforded 14 (68%, 0.110 g) as a bright yellow
solid; m.p. 249 °C. 1H NMR (500 MHz, CDCl3): δ = 9.28 (s, 1 H),
8.06 (s, 1 H), 8.00 (d, J = 8.1 Hz, 1 H), 7.86 (s, 1 H), 7.73 (d, J =
7.7 Hz, 1 H), 7.65 (t, J = 7.7 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H),
7.26 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
161.4 (dd, J = 251.0 and 11.2 Hz), 160.5 (dd, J = 260.0 and
13.1 Hz), 145.9, 143.6, 136.6, 134.4, 132.3, 131.3 (q, J = 10.6 Hz),
130.7, 130.3, 130.0, 125.4 (q, J = 4.1 Hz), 120.9, 118.1, 113.8, 104.5
(dd, J = 28.7 and 23.5 Hz), 103.3 (dd, J = 23.0 and 4.5 Hz) ppm.
C18H8F2N2S (322.33): calcd. C 67.07, H 2.50; found C 66.87, H
2.69.
4-(Furo[3,2-c]quinolin-2-yl)benzonitrile (20): The reaction of 4-bro-
mobenzonitrile (0.091 g, 0.5 mmol) and 6 (0.169 g, 1 mmol) over
18 h afforded 20 (82%, 0.110 g) as a light orange solid; m.p. 220 °C.
1H NMR (500 MHz, CDCl3): δ = 9.17 (s, 1 H), 8.32 (d, J = 8.2 Hz,
1 H), 8.22 (d, J = 8.2 Hz, 1 H), 7.98 (d, J = 8.5 Hz, 2 H), 7.75 (d,
J = 8.5 Hz, 2 H), 7.73 (t, J = 8.2 Hz, 1 H), 7.67 (t, J = 8.2 Hz, 1
H), 7.30 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 155.7,
153.9, 146.1, 145.4, 133.6, 132.7, 129.9, 128.8, 127.2, 125.0, 121.4,
119.9, 118.5, 116.8, 112.0, 103.4 ppm. C18H10N2O (270.28): calcd.
C 79.99, H 3.73; found C 79.84, H 3.61.
4-[8-(Trifluoromethyl)thieno[3,2-c]quinolin-2-yl]benzonitrile
(15):
The reaction of 4-bromobenzonitrile (0.091 g, 0.5 mmol) and 3
(0.253 g, 1 mmol) over 20 h afforded 15 (79%, 0.139 g) as a brown
solid; m.p. 247 °C. 1H NMR (500 MHz, CDCl3): δ = 9.36 (s, 1 H),
8.49 (s, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H),
7.91 (s, 1 H), 7.87 (d, J = 8.3 Hz, 2 H), 7.79 (d, J = 8.3 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 148.5, 145.4, 145.2,
143.6, 137.3, 135.2, 133.1, 131.7, 129.1 (q, J = 33 Hz), 127.0, 124.7
(q, J = 3.0 Hz), 123.2, 122.8 (q, J = 272.5 Hz), 121.3, 121.1 (q, J
= 4.2 Hz), 118.3, 112.4 ppm. C19H9F3N2S (354.35): calcd. C 64.40,
H 2.56; found C 64.51, H 2.70.
3-(Furo[3,2-c]quinolin-2-yl)benzonitrile (21): The reaction of 3-bro-
mobenzonitrile (0.091 g, 0.5 mmol) and 6 (0.169 g, 1 mmol) over
1
18 h afforded 21 (80%, 0.108 g) as a yellow solid; m.p. 202 °C. H
NMR (500 MHz, CDCl3): δ = 9.15 (s, 1 H), 8.31 (d, J = 7.8 Hz, 1
H), 8.20 (d, J = 8.2 Hz, 1 H), 8.15 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1
H), 7.72 (t, J = 8.2 Hz, 1 H), 7.69–7.63 (m, 2 H), 7.58 (t, J =
7.8 Hz, 1 H), 7.22 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 155.4, 153.6, 146.0, 145.3, 131.8, 130.9, 129.9, 129.8, 128.7, 128.6,
128.1, 127.2, 121.3, 119.9, 118.2, 116.8, 113.4, 102.3 ppm.
C18H10N2O (270.28): calcd. C 79.99, H 3.73; found C 79.78, H
3.89.
3-[8-(Trifluoromethyl)thieno[3,2-c]quinolin-2-yl]benzonitrile
(16):
The reaction of 3-bromobenzonitrile (0.091 g, 0.5 mmol) and 3
6750
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6745–6751

One-Pot Synthesis of Furo- or Thienoquinolines
Angew. Chem. Int. Ed. 2009, 48, 9792; g) C. Fischmeister, H.
Doucet, Green Chem. 2011, 13, 741.
[5] A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A.
Miyafuji, T. Nakata, N. Tani, Y. Aoyagi, Heterocycles 1990, 31,
1951.
[6] For selected examples of palladium-catalyzed intramolecular
cyclizations with heteroarenes, see: a) E. M. Beccalli, G. Brog-
gini, M. Martinelli, G. Paladino, C. Zoni, Eur. J. Org. Chem.
2005, 2091; b) L.-C. Campeau, M. Parisien, A. Jean, K. Fag-
nou, J. Am. Chem. Soc. 2006, 128, 581; c) A. Putey, L. Joucla,
L. Picot, T. Besson, B. Joseph, Tetrahedron 2006, 63, 867; d)
E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Synthesis 2008, 136; e) A. Mori, N. Arai, T. Hatta, D. Mongu-
chi, Heterocycles 2010, 80, 103.
8-Methyl-2-(naphthalen-2-yl)furo[3,2-c]quinoline (22): The reaction
of 2-bromonaphthalene (0.103 g, 0.5 mmol) and
9 (0.183 g,
1 mmol) over 15 h afforded 22 (87%, 0.135 g) as a brown oil. 1H
NMR (500 MHz, CDCl3): δ = 9.15 (s, 1 H), 8.47 (s, 1 H), 8.22 (s,
1 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.01–7.94 (m, 3 H), 7.89 (d, J =
7.7 Hz, 1 H), 7.60–7.54 (m, 3 H), 7.30 (s, 1 H), 2.67 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 156.3, 155.1, 144.4, 144.3, 137.1,
133.4, 130.4, 129.6, 128.8, 128.4, 127.9, 127.2, 126.9, 126.8, 125.5,
124.0, 122.6, 122.0, 119.0, 117.0, 101.0, 21.9 ppm. C22H15NO
(306.36): calcd. C 85.41, H 4.89; found C 85.51, H 4.67.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of new compounds.
[7] For a selection of recent contributions on direct arylations of
heteroaromatics from our laboratory, see: a) J. Roger, H. Dou-
cet, Adv. Synth. Catal. 2009, 351, 1977; b) F. Derridj, J. Roger,
S. Djebbar, H. Doucet, Org. Lett. 2010, 12, 4320; c) J. Roger,
Acknowledgments
F. Pozgan, H. Doucet, Adv. Synth. Catal. 2010, 352, 696; d) L.
ˇ
We thank the Centre National de la Recherche Scientifique
(CNRS), Region Bretagne, and Rennes Metropole for providing
financial support.
Chen, J. Roger, C. Bruneau, P. H. Dixneuf, H. Doucet, Chem.
Commun. 2011, 47, 1872; e) H. Y. Fu, H. Doucet, Eur. J. Org.
Chem. 2011, 7163; f) K. Beydoun, M. Zaarour, J. A. G. Wil-
liams, H. Doucet, V. Guerchais, Chem. Commun. 2012, 48,
1260.
[1] a) S. K. Kang, S. S. Park, S. S. Kim, J. K. Choi, E. K. Yum,
Tetrahedron Lett. 1999, 40, 4379; b) J.-K. Luo, M. J. Musmar,
R. N. Castle, J. Heterocycl. Chem. 1991, 28, 1309; c) E. A.-G.
Bakhite, Collect. Czech. Chem. Commun. 1992, 57, 2359; d) F.
Pierre, P. C. Chua, E. O’Brien, A. Siddiqui-Jain, P. Bourbon,
M. Haddach, J. Michaux, J. Nagasawa, M. K. Schwaebe, E.
Stefan, A. Vialettes, J. P. Whitten, T. K. Chen, L. Darjania, R.
Stansfield, K. Anderes, J. Bliesath, D. Drygin, C. Ho, M.
Omori, C. Proffitt, N. Streiner, K. Trent, W. G. Rice, D. M.
Ryckman, J. Med. Chem. 2011, 54, 635.
[2] a) Y. Yang, A.-B. Hörnfeldt, S. Gronowitz, J. Heterocycl.
Chem. 1989, 26, 865; b) B. S. Lee, J. H. Lee, D. Y. Chi, J. Org.
Chem. 2002, 67, 7884; c) J. Liu, Z. Diwu, W.-Y. Leung, Y. Lu,
B. Patch, R. P. Haugland, Tetrahedron Lett. 2003, 44, 4355; d)
E. David, S. Pellet-Rostaing, M. Lemaire, Tetrahedron 2007,
63, 8999; e) S. K. Ock, S. W. Youn, Bull. Korean Chem. Soc.
2010, 31, 704.
[3] For a review on heterocycle formation through intramolecular
palladium-catalyzed C–H bond functionalization, see: T.-S.
Mei, L. Kou, S. Ma, K. M. Engle, J.-Q. Yu, Synthesis 2012, 44,
1778.
[4] For reviews on palladium-catalyzed C–H bond functionaliza-
tions, see: a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev.
2007, 107, 174; b) T. Satoh, M. Miura, Chem. Lett. 2007, 36,
200; c) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36,
1173; d) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949; e) F.
Bellina, R. Rossi, Tetrahedron 2009, 65, 10269; f) L. Ackerm-
ann, R. Vincente, A. R. Kapdi, Angew. Chem. 2009, 121, 9976;
[8] For selected examples of palladium-catalyzed direct arylations
of thiophenes, see: a) T. Okazawa, T. Satoh, M. Miura, M.
Nomura, J. Am. Chem. Soc. 2002, 124, 5286; b) K. Kobayashi,
A. Sugie, M. Takahashi, K. Masui, A. Mori, Org. Lett. 2005,
7, 5083; c) H. A. Chiong, O. Daugulis, Org. Lett. 2007, 9, 1449;
d) M. Nakano, H. Tsurugi, T. Satoh, M. Miura, Org. Lett.
2008, 10, 1851; e) B. Liégault, D. Lapointe, L. Caron, A. Vlas-
sova, K. Fagnou, J. Org. Chem. 2009, 74, 1826; f) J. J. Dong, J.
Roger, H. Doucet, Tetrahedron Lett. 2009, 50, 2778; g) K.
Ueda, S. Yanagisawa, J. Yamaguchi, K. Itami, Angew. Chem.
2010, 122, 9130; Angew. Chem. Int. Ed. 2010, 49, 8946.
[9] J. E. Johnson, N. M. Morales, A. M. Gorczyca, D. Dolliver,
M. A. McAllister, J. Org. Chem. 2001, 66, 7979.
[10] For selected examples of palladium-catalyzed direct arylations
of furans, see: a) M. Parisien, D. Valette, K. Fagnou, J. Org.
Chem. 2005, 70, 7578; b) T. A. Dwight, N. R. Rue, D. Charyk,
R. Josselyn, B. DeBoef, Org. Lett. 2007, 9, 3137; c) E. M.
Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Synthesis
2008, 136; d) J. J. Dong, J. Roger, F. Pozgan, H. Doucet, Green
Chem. 2009, 11, 1832; e) B. Liégaut, D. Lapointe, L. Caron,
A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826; f) B.
Liegault, I. Petrov, S. I. Gorelsky, K. Fagnou, J. Org. Chem.
2010, 75, 1047; g) M. Ionita, J. Roger, H. Doucet, ChemSus-
Chem 2010, 3, 367; h) K. Si Larbi, H. Y. Fu, N. Laidaoui, K.
Beydoun, M. Miloudi, D. El Abed, S. Djebbar, H. Doucet,
ChemCatChem 2012, 4, 815.
Received: August 21, 2012
Published Online: October 25, 2012
Eur. J. Org. Chem. 2012, 6745–6751
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6751