Reactivity of 3-Bromofuran in Pd-Catalyzed C-H Bond Arylation toward the Synthesis of 2,3,5-Triarylfurans

Article abstract of DOI:10.1055/s-0037-1611819

Arylation of the C-H bond at the C2 position of 3-bromofuran is achieved using aryl bromides as coupling partners in the presence of phosphine-free Pd(OAc) ₂ /KOAc in DMA. This procedure gives C2,C5-di- and even C2,C4,C5-triarylated 3-bromofuran derivatives when larger amounts of aryl bromides are employed. In addition, C2,C3,C5-triarylated furans-containing three different aryl groups-are synthesized via a C2-H bond arylation/Suzuki reaction/C5-H bond arylation sequence.

Full text of DOI:10.1055/s-0037-1611819

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
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en
A. Sasmal et al.
Paper
Synthesis
Reactivity of 3-Bromofuran in Pd-Catalyzed C–H Bond Arylation
toward the Synthesis of 2,3,5-Triarylfurans
Arpan Sasmala
Thierry Roisnela
Jitendra K. Berab
Henri Doucet*a
Jean-François Soulé*a
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a Univ Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes,
France
Henri.doucet@univ-rennes1.fr
jean-francois.soule@univ-rennes1.fr
b Department of Chemistry and Center for Environmental
Science and Engineering, Indian Institute of Technology
Kanpur, Kanpur 208016, India
Received: 07.03.2019
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Accepted after revision: 06.04.2019
Published online: 07.05.2019
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DOI: 10.1055/s-0037-1611819; Art ID: ss-2019-t0157-op
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Abstract Arylation of the C–H bond at the C2 position of 3-bromo-
furan is achieved using aryl bromides as coupling partners in the pres-
ence of phosphine-free Pd(OAc)2/KOAc in DMA. This procedure gives
C2,C5-di- and even C2,C4,C5-triarylated 3-bromofuran derivatives
when larger amounts of aryl bromides are employed. In addition,
C2,C3,C5-triarylated furans—containing three different aryl groups—are
synthesized via a C2–H bond arylation/Suzuki reaction/C5–H bond aryl-
ation sequence.
HN
N
Me
Cl
N
O
Cl
OMe
azimilide
neurodazine
O
H
S
N
O
O
Key words palladium, furans, C–H bond arylation, aryl bromides
O
NH
Cl
F
N
N
lapatinib
Substituted furans are omnipresent in natural prod-
ucts,1 pharmaceuticals,2 (bio-sourced) polymeric materi-
als,3 and other functional molecules.4 They are also useful
synthetic intermediates.5 Arylated furans are important
frameworks embedded in many important pharmaceuticals
drugs. As examples, azimilide® is a class ΙΙΙ antiarrhythmic
drug, neurodazine® affects neuronal cell differentiation and
lapatinib® is an orally active drug for breast cancer and oth-
er solid tumors (Figure 1).
Therefore, the development of efficient and regioselec-
tive synthetic pathways for the preparation of multisubsti-
tuted furans is an important research area in heterocyclic
chemistry. Besides the traditional approaches involving cy-
clocondensation, cycloisomerization or multistep synthe-
sis,6 the direct functionalization of furan rings via palladi-
um-catalyzed C–H bond arylation is a modular approach to
access polyarylated furans.7 The first example of Pd-cata-
lyzed C2–H bond arylation of furan with activated aryl bro-
mides was reported in 1990 by Ohta and co-workers using
5 mol% of Pd(PPh3)4 associated with KOAc in DMA at 150 °C
(Scheme 1a).8 However, low to moderate yields in favor of
Figure 1 Examples of drugs containing a 2-arylfuran motif
the C2-arylated furans were often obtained due to the high
reactivity of the C5–H bond of C2-arylated furans leading to
the formation of C2,C5-diarylated furans.9 On the other
hand, the reactivity of C3-substituted furans has attracted
less attention. Controlling the regioselectivity of the C–H
bond arylation of ethyl 3-furoate depends on the reaction
conditions. In 2003, Sharp and co-workers reported C2 ary-
lation with electron-deficient aryl bromides using 5 mol%
of Pd(PPh3)4 associated with KOAc in non-polar solvents
such as toluene at 110 °C (Scheme 1b, right).10 In contrast,
they reported two examples of the C5-arylation of ethyl 3-
furoate using polar solvents, such as NMP, with Pd/C as the
catalyst (Scheme 1b, left).10 Later, Doucet and co-workers
also investigated the regioselectivity of the C–H bond aryla-
tion of ethyl 3-furoate and observed that using 0.2 mol% of
Pd(OAc)2/dppb in the presence of KOAc in DMA resulted in
C5-arylated furans being obtained as the major products
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
A. Sasmal et al.
Paper
Synthesis
a. Pd-catalyzed C2-arylation of furan (Ohta et al.)
Pd(PPh3)4 (5 mol%)
Br Ar
+
Ar
(7 examples)
KOAc, DMA, 150 °C
O
O
low to moderate yields
b. Pd-catalyzed C2- or C5-arylation of ethyl 3-furoate (Sharp et al.)
EtO2C
EtO2C
Ar
Pd(PPh3)4
(5 mol%)
Pd/C
(5 mol%)
EtO2C
O
(3 equiv)
+
O
KOAc
toluene, 110 °C
KOAc
NMP, 110 °C
Ar
O
(2 examples)
low yields
moderate yields
(5 examples)
Br Ar
c. Pd-catalyzed C5-arylation of ethyl 3-furoate (Doucet et al.)
Pd(OAc)2/dppb
(0.2 mol%)
EtO2C
EtO2C
EtO2C
Br Ar
+
+
Ar
KOAc, DMA
130 °C
Ar
O
O
O
minor
major
(2 equiv)
moderate yields
(2 examples)
d. Pd-catalyzed C2-arylation of 3-formylfuran (Doucet et al.)
1/2[PdCl(C3H5)]2/
Tedicyp
(1 mol%)
OHC
OHC
OHC
+
Br Ar
+
NaOAc, DMA
150 °C
O
O
10
O
MeO
OMe
(2 equiv)
90
74%
(1 example)
e. Reactivity of 3-bromofuran in Pd-catalyzed C–H bond arylation (this work)
Br
Br
Br
[Pd]
Br Ar
+
or
Ar
Ar
O
O
O
Scheme 1 Reactivity of (substituted) furan derivatives in Pd-catalyzed C–H bond arylation
along with the formation of C2-arylated furans as minor
products (Scheme 1c).11 Doucet and co-workers also report-
ed one example of the C2-arylation of 3-formylfuran using
a similar catalytic system (Scheme 1d).12 Conversely, the
chemoselective C–H bond arylations of thiophenes or pyra-
zoles, possessing bromo substituents at C3 or C4, with aryl
halides allowed the construction of polyarylated heteroaro-
matics.13 To the best of our knowledge, the reactivity of 3-
bromofuran in direct arylation has not been reported previ-
ously. Herein, we report our investigations on the coupling
of 3-bromofuran with electron-deficient aryl bromides and
on their polyarylation to construct triarylated furans
(Scheme 1e).
We selected 4-bromoacetophenone as the coupling
partner to investigate the chemoselectivity of the coupling
with 3-bromofuran. During development of the reaction,
we determined that the best conditions to regioselectively
obtain C2-arylated 3-bromofuran 1 in 47% yield were 1
mol% of Pd(OAc)2 as the catalyst and 2 equivalents of KOAc
as the base in DMA at 120 °C over 8 hours (Table 1, entry 1).
The regioselectivity of the arylation at the C2 position was
confirmed by X-ray crystal structure analysis of 1.14,15 The
amount of 3-bromofuran (5 equiv) was critical to isolate 1
in a good yield due to oligomerization as major side reac-
tion (Table 1, entries 1 and 2). The reaction time was also a
very important factor for this coupling, as shorter (4 h) or
longer reaction times (16 h) resulted in lower yields (Table
1, entries 3 and 4). A higher temperature of 150 °C led to
oligomerization, while at 80 °C a partial conversion of 4-
bromoacetophenone was observed (Table 1, entries 5 and
6). Palladium sources other than Pd(OAc)2 and different cat-
alyst loadings gave lower yields of 1 (Table 1, entries 7–11).
Reactions performed in other solvents such as cyclopentyl
methyl ether (CPME), 1,4-dioxane or pentan-1-ol failed to
afford the arylated furan 1 (Table 1, entries 12–14). The
concentration plays a major role in avoiding the oligomeri-
zation. Indeed, a concentration of 0.125 molar was deter-
mined to be the best choice; a concentration of 0.25 molar
afforded more oligomers, and when the reaction was per-
formed at 0.1 molar, only partial conversion was observed
(Table 1, entries 15 and 16). Finally, our attempts to inhibit
the degradation of 3-bromofuran by addition of TEMPO or
catechol were unsuccessful (Table 1, entries 17 and 18).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
A. Sasmal et al.
Paper
Synthesis
Table 1 Reaction Development
products. The reaction was slightly sensitive to steric hin-
drance, as from 2-bromobenzonitrile the coupling product
8 was isolated in only 42% yield. From less bulky and acti-
vated 3-bromo-2-fluorobenzaldehyde, Pd-catalyzed C2 ary-
lation led to the furan derivative 9 in 52% yield. Due to steric
factors, 2-bromonaphthalene displayed a higher reactivity
than 1-bromonaphthalene in the Pd-catalyzed C2 arylation
with 3-bromofuran. 3-Bromopyridine was also successfully
coupled with 3-bromofuran to afford 12 in good yield. Oth-
er N-heteroaryl bromides such as 5-bromopyrimidine and
3-bromoquinoline gave the C2-heteroarylated 3-bromofu-
ran derivatives 13 and 14 in 52% and 50% yields, respective-
ly.
Entry
Variation from standard conditions
Yield of 1 (%)a
Br
1
2
–
52 (47)
26
Br
Pd(OAc)2 (1 mol%)
R
R
+
Br
3 equiv of 3-bromofuran
4 h
KOAc (2 equiv)
DMA (4 mL)
120 °C, 8 h
O
O
3
32
(0.5 mmol)
2–14
Br
(5 equiv.)
4
16 h
49
Br
Br
5
150 °C
traces
22
O
6
80 °C
O
O
O
F3C
NC
7
PdCl2 (1 mol%)
48
Et
8
PdCl2(CH3CN)2 (1 mol%)
PdCl(C3H5)(dppb) (1 mol%)
Pd(OAc)2 (2 mol%)
Pd(OAc)2 (0.5 mol%)
cyclopentyl methyl ether (CPME)
1,4-dioxane
42
2 51%
Br
3 45%
4 42%
Br
Br
9
25
10
11
12
13
14
15
16
17
18
49
O
O
42
O
Cl
traces
traces
traces
29
F3C
NC
5 39%
6 50%
7 50%
Br
Br
Br
pentan-1-ol
OHC
DMA (2 mL)
O
O
O
DMA (5 mL)
42
CN
F
TEMPO (0.2 equiv) as additive
catechol (0.2 equiv) as additive
45
8 42%
9 52%
10 38%
Br
41
Br
a Determined by GC-MS analysis using n-dodecane as the internal standard.
Yield of isolated product is shown in parentheses.
O
O
N
Having determined the best conditions to selectively
arylate the C–H bond at the C2 position of 3-bromofuran
without cleavage of the C–Br bond on the furan ring, we
turned our attention to the scope of the aryl bromides
(Scheme 2). Firstly, the reactivity of a set of para-substitut-
ed aryl bromides was investigated. The reaction proceeded
smoothly using aryl bromides bearing an electron-with-
drawing group such as cyano, trifluoromethyl, propionyl, or
chloro, affording the C2-arylated 3-bromofurans 2–5 in
moderate yields. Notably, when non-activated aryl bro-
mides were employed (e.g., bromobenzene or 4-bromoan-
isole), the corresponding C2-arylated 3-bromofurans were
not obtained due to the oligomerization of 3-bromofuran.
meta-Substituted aryl bromides such as 3-bromobenzoni-
trile and 3-bromobenzotrifluoride were chemoselectively
coupled with 3-bromofuran to give the arylated compounds
6 and 7 in 50% yields, again without formation of diarylated
11 45%
12 45%
Br
Br
N
N
O
O
N
13 52%
14 50%
Scheme 2 Scope of the (hetero)aryl bromides in Pd-catalyzed direct
C2-arylation of 3-bromofuran
The C–H bond arylation of furan using palladium cataly-
sis often occurred at the C2 and C5 positions.8 We thus de-
cided to employ an excess amount of the aryl bromides to
have access to C2,C5-diarylated 3-bromofurans in one step
(Scheme 3). The reaction of 2 equivalents of 4-bromoben-
zonitrile and 3-bromofuran in the presence of 2 mol% of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
A. Sasmal et al.
Paper
Synthesis
Pd(OAc)2 and 3 equivalents of KOAc did not afford the de-
sired diarylated product 15; only the mono-arylated furan 2
was obtained, albeit in a poor yield. Surprisingly, in the
presence of 2 equivalents of 4-bromobenzotrifluoride, 3-
bromofuran was diarylated at the C2 and C5 positions to
give the furan 16 in 56% yield. This reactivity was also ob-
served with 2- and 3-bromobenzotrifluorides and 2-bro-
mo-6-(trifluoromethyl)pyridine, leading to the diarylated
furans 17–19 being selectively obtained in 47–53% yields. It
is noteworthy to mention that in all cases the formation of
mono-arylated 3-bromofurans was also observed in 5–10%
yields. The reason behind the outperformance of aryl bro-
mides bearing a trifluoromethyl group in multi-C–H bond
arylations remains unclear. However, similar phenomena
have been previously observed in the Pd-catalyzed multiple
C–H bond arylations of other heterocycles (e.g., thiophenes,
pyrroles, imidazoles and benzofuran).16
F3C
CF3
CF3
F3C
F3C
Br
Pd(OAc)2
(2 mol%)
Br
F3C
+
Br
KOAc (4 equiv)
DMA (4 mL)
120 °C, 8 h
O
O
F3C
(4 equiv)
(0.5 mmol)
CF3
20 61%
Scheme 4 Pd-catalyzed direct C2,C4,C5-triarylation of 3-bromofuran
with 1-bromo-3,5-bis(trifluoromethyl)benzene
We also tried to prepare 2,5-diarylated 3-bromofurans
with two different aryl units by iterative C–H bond aryl-
ations (Scheme 5). However, our attempts to selectively
arylate the C5–H bond of 3-bromo-2-(naphthalen-1-yl)fu-
ran (10) with 4-bromobenzonitrile remained unsuccessful,
even in the presence of the highly active diphosphine-palla-
dium complex [PdCl(C3H5)(dppb)]. Instead, a complex mix-
ture of side products was observed by GC-MS analysis,
which included debrominated products.
Br
Br
Pd(OAc)2 (2 mol%)
+
Br
KOAc (3 equiv)
DMA (4 mL)
120 °C, 8 h
R
O
O
R
Br
R
(2 equiv)
Br
(0.5 mmol)
15–19
Pd(OAc)2 or
Br
PdCl(C3H5)(dppb)
(2 mol%)
Br
Br
O
+
O
KOAc (2 equiv)
DMA (4 mL)
120 °C, 16 h
CN
O
O
F3C
CN
NC
CF3
CN
16 56%
21 not detected
15 trace (2 17%)
(1.5 equiv)
10 (0.5 mmol)
Br
Br
Br
O
O
O
O
O
CN
N
N
CF3
18 47%
F3C
F3C
CF3
F3C
CF3
side products detected by GC-MS analysis
17 53%
19 49%
Scheme 3 Scope of the (hetero)aryl bromides in Pd-catalyzed direct
C2,C5-diarylation of 3-bromofuran
Scheme 5 Reactivity of 3-bromo-2-(naphthalen-1-yl)furan (10)in a
Pd-catalyzed direct C5-arylation
We also performed the multiple C–H bond arylation of
3-bromofuran with 1-bromo-3,5-bis(trifluoromethyl)ben-
zene using 2 mol% of Pd(OAc)2 as the catalyst in DMA
(Scheme 4). In the presence of 2 equivalents of this aryl bro-
mide with 3 equivalents of base, the formation of triarylat-
ed furan 20 as well as the formation of a diarylated furan
were observed. Notably, we were not able to separate them
by flash chromatography. Furthermore, we setup the reac-
tion using 4 equivalents of 1-bromo-3,5-bis(trifluorometh-
yl)benzene to obtain selectively the triarylated furan 20 in a
good 61% yield.
Therefore, we decided to transform the C–Br bond into a
less reactive C–Ph bond to later investigate the reactivity of
the C5–H bond. From a mixture of 3-bromo-2-(naphthalen-
1-yl)furan (10) and phenylboronic acid (1.5 equiv) in the
presence of 2 mol% of a diphosphine-palladium catalyst and
2 equivalents of K3PO4 in dioxane at 100 °C over 16 hours,
the 2,3-diarylfuran 22 was obtained in 78% yield (Scheme
6).
Ph
Br
PdCl(C3H5)(dppb)
(2 mol%)
O
+
PhB(OH)2
(1.5 equiv)
O
K3PO4 (2 equiv)
1,4-dioxane (4 mL)
100 °C, 16 h
22 78%
10 (1 mmol)
Scheme 6 Reactivity of the C–Br bond of 3-bromo-2-(naphthalen-1-
yl)furan (10) in a Pd-catalyzed Suzuki reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
A. Sasmal et al.
Paper
Synthesis
Only a few methods are reported to prepare 2,3,5-tri-
arylfurans containing three different aryl groups and they
involve cyclization reactions.17 To the best of our knowl-
edge, there is no example of the direct arylation of 2,3-dia-
rylfurans. Therefore, we further demonstrated the potential
of this methodology with the introduction of a third aryl
group, by the sequential synthesis of 2,3,5-triarylfuran de-
rivatives containing three different aryl units (Scheme 7).
From a mixture of 2-naphthyl-3-phenylfuran (22) and 4-
bromobenzonitrile (1.5 equiv) in the presence of Pd-
Cl(C3H5)(dppb) (2 mol%) and KOAc as the base in DMA at
150 °C, the arylated product 23 was obtained in 71% yield.
The arylation took place at the most acidic C–H bond,
namely the C5 position. Similarly, the reaction with 3-bro-
moquinoline afforded the 2,3,5-triarylfuran 24 in 81% yield.
NAGEL silica gel (0.04–0.063 nm). 1H and 13C NMR spectra were re-
corded on a Bruker AV III 400 MHz NMR spectrometer equipped with
a BBFO probehead. Chemical shifts () are reported in parts per mil-
1
lion relative to residual chloroform (7.28 ppm for H; 77.23 ppm for
13C); coupling constants (J) are reported in Hertz. 1H NMR assignment
abbreviations are as follows: singlet (s), doublet (d), triplet (t), quartet
(q), doublet of doublets (dd), doublet of triplets (dt), and multiplet
(m). Elemental analyses were recorded using a Thermo Fisher FLASH
1112 instrument.
C2-Arylation of 3-Bromofuran; General Procedure
Reaction of the aryl bromide (0.5 mmol), 3-bromofuran (2.5 mmol, 5
equiv, 367 mg) and KOAc (1 mmol, 2 equiv, 98 mg) at 120 °C for 8 h in
DMA (4 mL) in the presence of Pd(OAc)2 (1 mol%, 0.005 mmol, 1.12
mg) (see Table 1 and Scheme 2) under argon afforded the arylation
product after evaporation of the solvent and purification on silica gel.
1-[4-(3-Bromofuran-2-yl)phenyl]ethan-1-one (1)
Ph
Ph
From 4-bromoacetophenone (100 mg, 0.5 mmol) and 3-bromofuran
(2.5 mmol, 5 equiv, 367 mg), product 1 was obtained in 47% (62 mg)
yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.11 (d, J = 8.7 Hz, 2 H), 8.04 (d,
J = 8.7 Hz, 2 H), 7.50 (d, J = 2.0 Hz, 1 H), 6.61 (d, J = 2.0 Hz, 1 H), 2.65 (s,
3 H).
Br
PdCl(C3H5)(dppb)
(2 mol%)
R
O
+
O
KOAc (2 equiv)
DMA (2 mL)
150 °C, 16 h
R
22 (0.5 mmol)
(1.5 equiv)
23 or 24
13C NMR (100 MHz, CDCl3, 25 °C):  = 197.6, 148.0, 142.9, 136.1,
Ph
Ph
134.0, 128.8, 125.3, 117.0, 98.5, 26.8.
Anal. Calcd for C12H9BrO2 (265.11): C, 54.37; H, 3.42. Found: C, 54.59;
H, 3.21.
O
O
CN
N
4-(3-Bromofuran-2-yl)benzonitrile (2)
23 71%
24 81%
From 4-bromobenzonitrile (91 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 2 was obtained in 51% (63 mg)
yield.
Scheme 7 Reactivity of 2-naphthyl-3-phenylfuran (22) in Pd-catalyzed
direct C5-arylation
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.09 (d, J = 8.4 Hz, 2 H), 7.69 (d,
J = 8.4 Hz, 2 H), 7.49 (d, J = 1.7 Hz, 1 H), 6.59 (d, J = 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 147.0, 143.3, 133.8, 132.5,
In summary, we have demonstrated that 3-bromofuran
is an attractive platform for the synthesis of polyarylated
furans. Firstly, conditions for the regioselective C2–H bond
arylation of 3-bromofuran with activated aryl bromides
were developed using phosphine-free Pd(OAc)2 as the cata-
lyst. Interestingly, the reaction was very chemoselective.
There was no formation of products resulting from the acti-
vation of the C–Br bond on the furan ring and this C–Br
bond remained untouched after the C2-arylation if the aryl
bromide contained an electron-withdrawing group. The use
of a larger amount of aryl bromide coupling partners al-
lowed access to C2,C5-diarylfurans, and even a C2,C4,C5-
triarylfuran in the case of 3,5-bis(trifluoromethyl)bromo-
benzene. Moreover, C2,C3,C5-triarylfurans containing three
different aryl units have been prepared in good yields via a
C2–H bond arylation/Suzuki cross-coupling/C5–H bond
arylation sequence.
125.6, 118.9, 117.1, 111.2, 99.3.
Anal. Calcd for C11H6BrNO (248.08): C, 53.26; H, 2.44. Found: C, 53.09;
H, 2.23.
3-Bromo-2-[4-(trifluoromethyl)phenyl]furan (3)
From 4-bromobenzotrifluoride (113 mg, 0.5 mmol) and 3-bromofu-
ran (367 mg, 2.5 mmol, 5 equiv), product 3 was obtained in 45% (65
mg) yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.12 (d, J = 8.4 Hz, 2 H), 7.70 (d,
J = 8.4 Hz, 2 H), 7.50 (d, J = 1.9 Hz, 1 H), 6.61 (d, J = 1.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 147.5, 142.6, 132.9, 128.4, 125.5
(q, J = 4.1 Hz), 125.4, 124.0 (q, J = 274.2 Hz), 116.6, 98.0.
19F NMR (376 MHz, CDCl3, 25 °C):  = –62.7 (s).
Anal. Calcd for C11H6BrF3O (291.07): C, 45.39; H, 2.08. Found: C,
45.51; H, 2.34.
1-[4-(3-Bromofuran-2-yl)phenyl]propan-1-one (4)
From 4-bromopropiophenone (107 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 4 was obtained in 42% (59 mg)
yield.
All reactions were carried out under an argon atmosphere using stan-
dard Schlenk techniques. DMA was purchased from Acros Organics
and was not purified before use. All reagents were weighed and han-
dled in air. Column chromatography was performed with MACHEREY-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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A. Sasmal et al.
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1H NMR (400 MHz, CDCl3, 25 °C):  = 8.08 (d, J = 8.8 Hz, 2 H), 8.02 (d,
J = 8.9 Hz, 2 H), 7.47 (d, J = 1.9 Hz, 1 H), 6.58 (d, J = 1.9 Hz, 1 H), 3.02 (q,
J = 7.2 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3 H).
3-(3-Bromofuran-2-yl)-4-fluorobenzaldehyde (9)
From 4-bromo-2-fluorobenzaldehyde (102 mg, 0.5 mmol) and 3-bro-
mofuran (367 mg, 2.5 mmol, 5 equiv), product 9 was obtained in 52%
(70 mg) yield.
13C NMR (100 MHz, CDCl3, 25 °C):  = 200.3, 148.0, 142.9, 135.9,
1H NMR (400 MHz, CDCl3, 25 °C):  = 10.00 (s, 1 H), 8.24 (dd, J = 2.1,
6.9 Hz, 1 H), 7.93 (ddd, J = 2.2, 4.8, 8.5 Hz, 1 H), 7.53 (d, J = 1.9 Hz, 1 H),
7.40–7.24 (m, 1 H), 6.60 (d, J = 2.0 Hz, 1 H).
133.8, 128.4, 125.4, 116.9, 98.4, 32.0, 8.4.
Anal. Calcd for C13H11BrO2 (279.13): C, 55.94; H, 3.97. Found: C, 56.11;
H, 4.05.
13C NMR (100 MHz, CDCl3, 25 °C):  = 190.2, 163.0 (d, J = 263.4 Hz),
144.6 (d, J = 2.3 Hz), 143.8, 132.9 (d, J = 3.1 Hz), 132.8 (d, J = 4.6 Hz),
131.7 (d, J = 9.9 Hz), 118.9 (d, J = 14.7 Hz), 117.7 (d, J = 23.0 Hz), 115.8,
100.2.
3-Bromo-2-(4-chlorophenyl)furan (5)
From 1-bromo-4-chlorobenzene (96 mg, 0.5 mmol) and 3-bromofu-
ran (367 mg, 2.5 mmol, 5 equiv), product 5 was obtained in 39% (50
mg) yield.
19F NMR (376 MHz, CDCl3, 25 °C):  = –100.9 (s)
1H NMR (400 MHz, CDCl3, 25 °C):  = 7.90 (d, J = 8.7 Hz, 2 H), 7.42 (d,
J = 1.9 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 2 H), 6.54 (d, J = 1.9 Hz, 1 H).
Anal. Calcd for C11H6BrFO2 (269.07): C, 49.10; H, 2.25. Found: C,
49.38; H, 2.44.
13C NMR (100 MHz, CDCl3, 25 °C):  = 148.1, 142.1, 133.9, 128.9,
128.4, 126.9, 116.5, 96.6.
3-Bromo-2-(naphthalen-1-yl)furan (10)
From 1-bromonaphthalene (103 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 10 was obtained in 38% (52 mg)
yield.
Anal. Calcd for C10H6BrClO (257.51): C, 46.64; H, 2.35. Found: C,
46.36; H, 2.57.
3-(3-Bromofuran-2-yl)benzonitrile (6)
1H NMR (400 MHz, CDCl3, 25 °C):  = 7.98–7.90 (m, 3 H), 7.73 (dd, J =
1.3, 7.1 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 7.59–7.53 (m, 3 H), 6.68 (d,
J = 2.0 Hz, 1 H).
From 3-bromobenzonitrile (91 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 6 was obtained in 50% (62 mg)
yield.
13C NMR (100 MHz, CDCl3, 25 °C):  = 150.5, 142.8, 133.9, 131.7,
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.26 (t, J = 1.3 Hz, 1 H), 8.20 (td,
J = 1.3, 7.7 Hz, 1 H), 7.60 (td, J = 1.3, 7.7 Hz, 1 H), 7.53 (t, J = 7.7 Hz, 1
H), 7.47 (d, J = 1.9 Hz, 1 H), 6.58 (d, J = 1.9 Hz, 1 H).
130.0, 129.0, 128.5, 126.8, 126.3, 126.1, 125.1, 115.3, 99.1.
Anal. Calcd for C14H9BrO (273.13): C, 61.57; H, 3.32. Found: C, 61.46;
H, 3.28.
13C NMR (100 MHz, CDCl3, 25 °C):  = 146.7, 142.9, 131.2, 131.1,
129.6, 129.4, 128.9, 118.7, 116.8, 113.1, 98.2.
3-Bromo-2-(naphthalen-2-yl)furan (11)
From 2-bromonaphthalene (103 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 11 was obtained in 45% (61 mg)
yield.
Anal. Calcd for C11H6BrNO (248.08): C, 53.26; H, 2.44. Found: C, 53.41;
H, 2.36.
3-Bromo-2-[3-(trifluoromethyl)phenyl]furan (7)
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.45 (s, 1 H), 8.08 (dd, J = 1.8, 8.7
Hz, 1 H), 7.94–7.86 (m, 2 H), 7.86–7.81 (m, 1 H), 7.54–7.45 (m, 3 H),
6.59 (d, J = 2.0 Hz, 1 H).
From 3-bromobenzotrifluoride (113 mg, 0.5 mmol) and 3-bromofu-
ran (367 mg, 2.5 mmol, 5 equiv), product 7 was obtained in 50% (73
mg) yield.
13C NMR (100 MHz, CDCl3, 25 °C):  = 149.2, 142.1, 133.3, 132.9,
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.22 (s, 1 H), 8.17 (d, J = 7.8 Hz, 1
H), 7.63–7.51 (m, 2 H), 7.46 (d, J = 2.0 Hz, 1 H), 6.57 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 147.6, 142.6, 131.4, 130.6,
129.2, 128.5, 124.6 (q, J = 3.9 Hz), 124.1 (q, J = 274.1 Hz), 122.3 (q, J =
4.0 Hz), 116.7, 97.5.
128.6, 128.3, 127.8, 127.3, 126.6, 126.6, 124.9, 123.4, 116.6, 96.6.
Anal. Calcd for C14H9BrO (273.13): C, 61.57; H, 3.32. Found: C, 61.79;
H, 3.51.
3-(3-Bromofuran-2-yl)pyridine (12)
19F NMR (376 MHz, CDCl3, 25 °C):  = –62.9 (s).
From 3-bromopyridine (79 mg, 0.5 mmol) and 3-bromofuran (367
mg, 2.5 mmol, 5 equiv), product 12 was obtained in 45% (50 mg) yield.
Anal. Calcd for C11H6BrF3O (291.07): C, 45.39; H, 2.08. Found: C,
45.56; H, 2.21.
1H NMR (400 MHz, CDCl3, 25 °C):  = 9.23 (br s, 1 H), 8.57 (br s, 1 H),
8.38–8.11 (m, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.36 (dd, J = 4.8, 8.2 Hz, 1
H), 6.57 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 148.8, 146.8, 146.5, 142.9,
132.5, 123.5, 116.6, 97.8.
2-(3-Bromofuran-2-yl)benzonitrile (8)
From 2-bromobenzonitrile (91 mg, 0.5 mmol) and 3-bromofuran
(367 mg, 2.5 mmol, 5 equiv), product 8 was obtained in 42% (52 mg)
yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 7.92 (d, J = 7.4 Hz, 1 H), 7.77 (d,
J = 7.9 Hz, 1 H), 7.65 (td, J = 1.3, 7.9 Hz, 1 H), 7.57 (d, J = 1.9 Hz, 1 H),
7.46 (td, J = 1.3, 7.7 Hz, 1 H), 6.61 (d, J = 1.9 Hz, 1 H).
Anal. Calcd for C9H6BrNO (224.06): C, 48.25; H, 2.70. Found: C, 48.21;
H, 2.83.
5-(3-Bromofuran-2-yl)pyrimidine (13)
13C NMR (100 MHz, CDCl3, 25 °C):  = 146.7, 143.7, 134.5, 132.5,
From 5-bromopyrimidine (79 mg, 0.5 mmol) and 3-bromofuran (367
mg, 2.5 mmol, 5 equiv), product 13 was obtained in 52% (58 mg) yield.
132.3, 129.4, 128.8, 118.2, 116.2, 111.0, 99.8.
1H NMR (400 MHz, CDCl3, 25 °C):  = 9.34 (s, 2 H), 9.18 (s, 1 H), 7.53
(d, J = 2.0 Hz, 1 H), 6.62 (d, J = 2.0 Hz, 1 H).
Anal. Calcd for C11H6BrNO (248.08): C, 53.26; H, 2.44. Found: C, 53.20;
H, 2.49.
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A. Sasmal et al.
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13C NMR (100 MHz, CDCl3, 25 °C):  = 157.3, 153.0, 144.0, 143.9,
3-Bromo-2,5-bis[2-(trifluoromethyl)phenyl]furan (18)
124.6, 116.8, 99.5.
From 2-bromobenzotrifluoride (223 mg, 1 mmol, 2 equiv) and 3-bro-
mofuran (73 mg, 0.5 mmol, 1 equiv), product 18 was obtained in 47%
(102 mg) yield.
Anal. Calcd for C8H5BrN2O (225.05): C, 42.70; H, 2.24. Found: C, 42.96;
H, 2.37.
1H NMR (400 MHz, CDCl3, 25 °C):  = 7.89–7.81 (m, 2 H), 7.80–7.73
3-(3-Bromofuran-2-yl)quinoline (14)
(m, 2 H), 7.70–7.53 (m, 3 H), 7.50–7.41 (m, 1 H), 6.93 (s, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 150.4, 148.2, 132.5, 132.1,
131.7, 130.0, 129.7, 129.6 (q, J = 31.5 Hz), 128.6, 127.1 (q, J = 5.4 Hz),
126.7 (q, J = 5.9 Hz), 126.7 (q, J = 31.2 Hz), 123.9 (q, J = 271.6 Hz),
123.8 (q, J = 271.6 Hz), 115.2 (q, J = 4.7 Hz), 100.5.
From 3-bromoquinoline (104 mg, 0.5 mmol) and 3-bromofuran (367
mg, 2.5 mmol, 5 equiv), product 14 was obtained in 50% (69 mg) yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 9.50 (d, J = 2.3 Hz, 1 H), 8.69 (d,
J = 2.3 Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.73 (t,
J = 6.8 Hz, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.52 (d, J = 2.0 Hz, 1 H), 6.61 (d,
J = 2.0 Hz, 1 H).
19F NMR (376 MHz, CDCl3, 25 °C):  = –59.6, –60.0.
Anal. Calcd for C18H9BrF6O (435.16): C, 49.68; H, 2.08. Found: C,
49.58; H, 2.34.
13C NMR (100 MHz, CDCl3, 25 °C):  = 147.7, 147.2, 146.9, 143.0,
131.8, 130.0, 129.4, 128.3, 127.6, 127.4, 123.3, 116.7, 98.0.
Anal. Calcd for C13H8BrNO (274.12): C, 56.96; H, 2.94. Found: C, 57.08;
H, 2.69.
6,6′-(3-Bromofuran-2,5-diyl)bis[2-(trifluoromethyl)pyridine] (19)
From 2-bromo-6-trifluoromethylpyridine (192 mg, 1 mmol, 2 equiv)
and 3-bromofuran (73 mg, 0.5 mmol, 1 equiv), product 19 was ob-
tained in 49% (107 mg) yield.
C2,C5-Diarylation of 3-Bromofuran; General Procedure
1H NMR (300 MHz, CDCl3, 25 °C):  = 8.19 (d, J = 8.1 Hz, 1 H), 8.05–
7.93 (m, 3 H), 7.67–7.59 (m, 2 H), 7.44 (s, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 152.6, 148.5, 148.5 (q, J = 25.3
Hz), 148.2, 148.2 (q, J = 25.9 Hz), 147.6, 138.3, 138.0, 122.8, 121.3,
121.3 (q, J = 274.5 Hz), 121.2 (q, J = 274.5 Hz), 119.3 (t, J = 2.9 Hz),
119.0 (q, J = 2.7 Hz), 116.9, 103.3.
Reaction of the aryl bromide (1 mmol), 3-bromofuran (0.5 mmol, 1
equiv, 73 mg) and KOAc (1.5 mmol, 3 equiv, 147 mg) at 120 °C for 8 h
in DMA (2 mL) in the presence of Pd(OAc)2 (2 mol%, 0.01 mmol, 2.24
mg,) (see Table 1 or Scheme 3) under argon afforded the diarylation
product after evaporation of the solvent and purification on silica gel.
3-Bromo-2,5-bis[4-(trifluoromethyl)phenyl]furan (16)
19F NMR (376 MHz, CDCl3, 25 °C):  = –68.2 (s), –68.3 (s).
From 4-bromobenzotrifluoride (223 mg, 1 mmol, 2 equiv) and 3-bro-
mofuran (73 mg, 0.5 mmol, 1 equiv), product 16 was obtained in 56%
(122 mg) yield.
Anal. Calcd for C16H7BrF6N2O (437.14): C, 43.96; H, 1.61. Found: C,
44.09; H, 1.98.
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.17 (d, J = 8.8 Hz, 2 H), 7.80 (d,
J = 8.3 Hz, 2 H), 7.75–7.66 (m, 4 H), 6.93 (s, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 152.0, 147.7, 132.5, 132.4, 130.2
(q, J = 29.3 Hz), 129.9 (q, J = 28.4 Hz), 126.0 (q, J = 3.9 Hz), 125.6 (q, J =
3.9 Hz), 125.5, 124.1, 124.0 (q, J = 273.5 Hz), 123.9 (q, J = 273.5 Hz),
113.4, 100.0.
2,3,5-Tris[3,5-bis(trifluoromethyl)phenyl)]-4-bromofuran (20)
The reaction of 1-bromo-3,5-bis(trifluoromethyl)benzene (586 mg, 2
mmol, 4 equiv), 3-bromofuran (73 mg, 0.5 mmol, 1 equiv) and KOAc
(180 mg, 3 mmol, 4 equiv) at 120 °C for 8 h in DMA (2 mL) in the pres-
ence of Pd(OAc)2 (2.24 mg, 0.01 mmol, 2 mol%) under argon afforded,
after evaporation of the solvent and purification, product 20 in 61%
(239 mg) yield.
19F NMR (376 MHz, CDCl3, 25 °C):  = –62.7 (s), –62.7 (s).
1H NMR (300 MHz, CDCl3, 25 °C):  = 8.52 (s, 2 H), 8.05 (s, 1 H), 7.95
(s, 1 H), 7.89 (s, 2 H), 7.84 (s, 1 H), 7.82 (s, 2 H).
Anal. Calcd for C18H9BrF6O (435.16): C, 49.68; H, 2.08. Found: C,
49.67; H, 2.00.
13C NMR (100 MHz, CDCl3, 25 °C):  = 147.6, 147.5, 133.2 (q, J = 34.7
Hz), 132.9 (q, J = 35.1 Hz), 132.8 (q, J = 35.2 Hz), 132.6, 130.5, 130.5
(m), 130.4, 126.0 (m), 125.8 (m) 125.2, 123.2 (q, J = 273.1 Hz), 123.2
(m), 123.0 (q, J = 273.1 Hz), 122.8 (q, J = 3.8 Hz), 122.8 (q, J = 273.1 Hz),
103.0.
3-Bromo-2,5-bis[3-(trifluoromethyl)phenyl]furan (17)
From 3-bromobenzotrifluoride (223 mg, 1 mmol, 2 equiv) and 3-bro-
mofuran (73 mg, 0.5 mmol, 1 equiv), product 17 was obtained in 53%
(115 mg) yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.30 (s, 1 H), 8.26–8.19 (m, 1 H),
19F NMR (376 MHz, CDCl3, 25 °C):  = –63.0 (s), –63.1 (s), –63.5 (s).
7.92 (s, 1 H), 7.87 (dt, J = 2.0, 5.8 Hz, 1 H), 7.66–7.52 (m, 4 H), 6.90 (s, 1
H).
Anal. Calcd for C28H9BrF18O (783.25): C, 42.94; H, 1.16. Found: C,
42.75; H, 1.01.
13C NMR (100 MHz, CDCl3, 25 °C):  = 152.0, 147.6, 131.7 (q, J = 25.4
Hz), 131.3 (d, J = 25.3 Hz), 130.2, 130.2, 129.7, 129.3, 128.6 (m), 127.2
(m), 125.1 (q, J = 3.8 Hz), 124.9 (q, J = 3.8 Hz), 124.1 (q, J = 273.2 Hz),
124.0 (q, J = 273.2 Hz), 122.3 (q, J = 4.0 Hz), 120.9 (d, J = 3.9 Hz), 112.9,
99.6.
2-(Naphthalen-1-yl)-3-phenylfuran (22)
The reaction of 3-bromo-2-(naphthalen-1-yl)furan (10) (271 mg, 1
mmol), phenylboronic acid (180 mg, 1.5 mmol) and K3PO4 (424 mg, 2
mmol) at 80 °C over 16 h in 1,4-dioxane (4 mL) in the presence of Pd-
Cl(C3H5)(dppb) (12 mg, 0.02 mmol) under argon afforded, after evap-
oration of the solvent and purification on silica gel, product 22 in 78%
(211 mg) yield.
19F NMR (376 MHz, CDCl3, 25 °C):  = –62.9 (s), –62,9 (s).
Anal. Calcd for C18H9BrF6O (435.16): C, 49.68; H, 2.08. Found: C,
49.89; H, 1.97.
1H NMR (300 MHz, CDCl3, 25 °C):  = 7.94–7.88 (m, 2 H), 7.84 (d, J =
8.4 Hz, 1 H), 7.64 (d, J = 1.9 Hz, 1 H), 7.54–7.45 (m, 2 H), 7.45–7.37 (m,
2 H), 7.24–7.18 (m, 2 H), 7.18–7.12 (m, 3 H), 6.82 (d, J = 1.9 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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13C NMR (100 MHz, CDCl3, 25 °C):  = 148.5, 142.4, 133.9, 133.4,
132.0, 129.3, 129.1, 128.9, 128.4, 128.3, 127.6, 126.6, 126.5, 126.1,
125.3, 123.8, 111.7.
References
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Anal. Calcd for C20H14O (270.33): C, 88.86; H, 5.22. Found: C, 88.96; H,
5.35.
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C5-Arylation of 2-(Naphthalen-1-yl)-3-phenylfuran (22); General
Procedure
Reaction of the aryl bromide (0.75 mmol), 2-(naphthalen-1-yl)-3-
phenylfuran (22) (0.5 mmol, 1 equiv) and KOAc (1 mmol, 2 equiv, 98 mg)
at 120 °C for 16 h in DMA (2 mL) in the presence of PdCl(C3H5)(dppb)
(12 mg, 0.02 mmol) (see Scheme 7) under argon afforded the aryl-
ation product after evaporation of the solvent and purification on sili-
ca gel.
4-[5-(Naphthalen-1-yl)-4-phenylfuran-2-yl]benzonitrile (23)
From 4-bromobenzonitrile (137 mg, 0.75 mmol, 1.5 equiv) and 2-
(naphthalen-1-yl)-3-phenylfuran (22) (135 mg, 0.5 mmol, 1 equiv),
product 23 was obtained in 71% (132 mg) yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 8.00–7.92 (m, 3 H), 7.86 (d, J =
8.5 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H), 7.59 (ddd, J = 1.3, 7.6, 8.1 Hz, 1 H),
7.56–7.50 (m, 2 H), 7.50–7.42 (m, 1 H), 7.32–7.20 (m, 6 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 151.6, 149.9, 134.5, 134.1,
132.8, 132.8, 131.8, 130.0, 129.2, 128.7, 128.6, 128.4, 127.7, 127.3,
126.9, 126.6, 126.4, 126.0, 125.4, 124.1, 119.1, 110.5, 110.3.
Anal. Calcd for C27H17NO (371.44): C, 87.31; H, 4.61. Found: C, 87.45;
H, 4.81.
3-[5-(Naphthalen-1-yl)-4-phenylfuran-2-yl]quinoline (24)
From 3-bromoquinoline (156 mg, 0.75 mmol, 1.5 equiv) and 2-(naph-
thalen-1-yl)-3-phenylfuran (22) (135 mg, 0.5 mmol, 1 equiv), product
24 was obtained in 81% (161 mg) yield.
1H NMR (400 MHz, CDCl3, 25 °C):  = 9.38 (d, J = 2.1 Hz, 1 H), 8.48 (s, 1
H), 8.17 (d, J = 9.1 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.97 (t, J = 7.1 Hz, 2
H), 7.85 (d, J = 8.2 Hz, 1 H), 7.77–7.64 (m, 2 H), 7.58–7.51 (m, 4 H),
7.35 (d, J = 7.5 Hz, 3 H), 7.31–7.20 (m, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C):  = 150.9, 149.2, 146.9, 146.9,
134.0, 132.8, 131.8, 129.7, 129.5, 129.3, 129.2, 129.1, 128.6, 128.5,
128.4, 128.0, 128.0, 127.6, 127.4, 127.4, 127.1, 126.7, 126.2, 126.0,
125.4, 123.9, 108.8.
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Funding Information
A.S. acknowledges the Indo-French Centre for the Promotion of Ad-
vanced Research (IFCPAR, No. 5705-1) for a Ph.D. grant and research
support. We also thank the CNRS and ‘Rennes Metropole’ for provid-
ing financial support.
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c
e
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(5
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611819.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I