Palladium-catalyzed direct arylation reaction of 2,3,5-trisubstituted furans with aryl iodides or aryl bromides

Article abstract of DOI:10.1055/s-0030-1260763

Pd-catalyzed direct arylation of 2,3,5-trisubstituted furans with a variety of aryl iodides or aryl bromides that showed high activity with reasonably broad scope was developed. Under optimal conditions, all reactions gave the desired products in moderate

Full text of DOI:10.1055/s-0030-1260763

1472
LETTER
Palladium-Catalyzed Direct Arylation Reaction of 2,3,5-Trisubstituted Furans
with Aryl Iodides or Aryl Bromides
D
irec
t
A
rylation R
u
eaction of 2,
a
3,5-Trisubstitute
d
C
Furans ao,* Dongsheng Shen, Haiying Zhan, Liuqing Yang
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. of China
Fax +86(760)88207939; E-mail: hua.cao@mail.scut.edu.cn
Received 26 February 2011
their attention on the transition-metal-catalyzed reactions
Abstract: Pd-catalyzed direct arylation of 2,3,5-trisubstituted
to develop novel and convenient direct arylation of
heteroarenes for the synthesis of biaryl compounds. Al-
furans with a variety of aryl iodides or aryl bromides that showed
high activity with reasonably broad scope was developed. Under
though several methodologies have been developed to
synthesize biaryl compouds during the last decades, there
is still an intrinsic need to develop new arylation of het-
eroarenes for the synthesis of more diverse biaryl com-
pounds under mild conditions and simple catalytic
systems.
optimal conditions, all reactions gave the desired products in mod-
erate to good yields.
Key words: palladium, arylation reaction, 2,3,5-trisubstituted
furans, aryl iodides, aryl bromides
The transition-metal-catalyzed direct arylation reaction to
form C–C bonds is one of the most powerful tools for the
preparation of complex biaryl compounds under mild
conditions.1 Development of new transition-metal-cata-
lyzed approaches to construct biaryl compounds for their
syntheses is currently a popular research area. Recently,
the vast majority of direct arylation reactions were carried
out to construct biaryl compounds by Pd,2 Rh,3 Ru4 triad.
And there were also several reviews on the subject of C–
H direct arylation,5 many focusing on areas such as cata-
lyzed arylation toward direct arylation of heterocycles,6
intermolecular direct arylation reactions,7 and synthesis of
polyarenes.8 Among these new approaches and methodo-
gies, palladium was probably the most versatile and wide-
ly used metal for diect arylation to synthesize diaryl
compounds. Over the past decades, palladium-catalyzed
direct C–H bond functionalization became a highly attrac-
tive strategy to form C–C bonds in organic synthesis9 and
represented a highly desirable goal.10 This was mainly due
to palladium’s relatively lower cost and better perfor-
mance in autocatalysts. In this paper, we describe an effi-
cient Pd-catalyzed direct arylation process to construct
biaryl compounds.
In the current study, we report our new finding which was
a facile direct arylation reaction for the synthesis of biaryl
compounds from aryl halides(X = I, Br) with 2,3,5-trisub-
stituted furans (Scheme 1).
R1
R1
Ar
cat. additive
solvent
+
Ar
X
R1
R1
R2
R2
O
O
Scheme 1 Arylation of furans with aryl halides
Diethyl 5-formylfuran-2,3-dicarboxylate (1a) and iodo-
benzene (2a) were chosen as model substrates to optimize
the reaction conditions for the formation of biaryl com-
pounds in our initial study (Table 1). Various palladium
catalysts were firstly examined for the direct arylation
process. As demonstrated in Table 1, we were pleased to
observe that the desired product 3a was formed in 36%
yield in the presence of PdCl2 and Cs2CO3 (Table 1, entry
1) in N,N-dimethylformamide (DMF) for 20 hours at 100
°C. Undoubtedly, palladium was an efficient catalyst for
this transformation. Thus, other palladium catalysts, such
as Pd(OAc)2 and Pd(dba)2, were also employed in this re-
action, and the arylation product 3a was obtained in 59%,
33% yields, respectively(Table 1, entries 2 and 3). Stimu-
lated by these results, a variety of ligands, such as
DABCO, Ph3P, and PBu3, were also tested in the next step
in the presence of Pd(OAc)2 and Cs2CO3 at 100 °C for 20
hours (Table 1, entries 4–6). Interestingly, the reaction
yield of 3a was dramatically increased to 79% (Table 1,
entry 4) by using Ph3P as ligand. Solvent effects were also
investigated in the following tests. It was found that ary-
lation product 3a could be isolated in very good yields in
DMA (Table 1, entry 7), but when THF, benzene, toluene,
and dimethyl sulfoxide (DMSO) were employed, the reac-
tion was severely retarded (Table 1, entries 8–11). Final-
ly, the effects of temperature were also detected (Table 1,
entries 12–15), and it was evident that 120 °C was the
most optimal temperature for this transformation.
Biaryl compounds were always one of the most important
class of organic molecules11 because of the abundance of
the biaryl structural motif in natural products, in biologi-
cally active molecules,12 and in materials chemistry. As a
pharmacophore, those compounds exhibited a wide range
of biological activities such as antibiotic, anti-inflamma-
tory, anticancer, and antifungal.13 Due to their wide range
of practical applications, the development of new efficient
and convenient methods for the arylation of heterocycles
still remains a challenging goal. Therefore, more and
more synthetic organic chemists have focused much of
SYNLETT 2011, No. 10, pp 1472–1476
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260763; Art ID: W05611ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Arylation Reaction of 2,3,5-Trisubstituted Furans
1473
Table 1 Condition Screening for the Palladium-Catalyzed Direct
Arylation Reaction of 1a with 2aa
bromides were obtained in lower yields. Similarly, 1b was
also employed, and the products were also obtained in
good yield.
EtO2C
EtO2C
Ph
cat. additive
solvent
I
+
The catalytic system was also found to be useful for car-
rying out arylation reactions of diethyl 5-methylfuran-2,3-
dicarboxylate (1c) with aryl iodides or aryl bromides. This
indicated that most aryl iodides or aryl bromides with dif-
ferent substituent groups presented on the aromatic ring
could react smoothly, and the corresponding products
were obtained in moderate to good yields in the presence
of Pd(OAc)2/Ph3P catalytic system. However, in compar-
ison to 1a and 1b, arylation products prepared from 1c
were obtained in lower yields.
EtO2C
EtO2C
CHO
CHO
O
O
1a
2a
3a
Entry Catalyst
Additive
Solvent
Temp Yield
(°C)
100
100
100
100
100
100
100
(%)b
1
2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
36
Pd(OAc)2
Pd(dba)2
59
3
33
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ph3P/Cs2CO3
Bu3P/Cs2CO3
79
A plausible mechanism for the direct arylation reaction is
described in Scheme 2. A mechanism similar to those of
previous studies on the arylation of heterocycles2i may be
involved in the present reaction. First, intermediate A was
formed from the reaction of 1 with the palladium species.
Intermediate A then converted to intermediate via the ab-
straction of the acidic hydrogen in B with the help of
Cs2CO3. Finally, reductive elimination of B gives the de-
sired products 3 and releases the Pd catalyst.
5
65
6
DABCO/Cs2CO3 DMF
67
7
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
Ph3P/Cs2CO3
DMA
THF
83
8
reflux 30
9
benzene
toluene
DMSO
DMA
DMA
DMA
DMA
100
100
100
110
120
150
r.t.
70
72
79
84
89
80
–
10
11
12
13
14
15
R1
Ar
PdLn
ArX
2
R1
R2
O
3
Ar
R1
PdLn
Ar
X
PdLn
B
R1
R2
R1
a Reactions conditions: 1a (0.5 mmol), aryl iodide (0.7 mmol), Pd cat-
O
alyst (5 mol%), Cs2CO3 (1.0 mmol), ligand (10 mol%), solvent (4
mL), 20 h.
R1
R2
b GC yields.
O
Ar
R1
1
PdLn
Cs2CO3
H
R2
+
With the optimal reaction conditions in hand, we explored
the scope of this arylation reaction (Table 2). By using 1a
as the substrate, we carried out the reactions with various
types of aryl iodides and aryl bromides (X = I, Br;
Table 2, entries 1–6). In general, all reactions were very
clean, and the arylation products 3 were obtained in good
yields especially those using aryl iodides under the opti-
mized conditions. These results indicated that all aryl io-
dides, regardless of their electronic or steric properties,
proceeded smoothly to afford the expected biaryls in good
yields. Meanwhile, higher isolated yields were obtained
when electron-withdrawing substituents were on the aro-
matic ring (Table 2, entry 5), and sterically demanding
ortho substituents did not hamper the arylation reaction
(Table 2, entry 3). It was especially noteworthy that this
direct arylation reaction could take place and gave moder-
ate yields by using 1a and aryl bromides. Obviously, com-
pared with the aryl iodides, arylation products using aryl
R1
O
A
Scheme 2 Plausible mechanism for the arylation of 1 with 2
In summary, an efficient palladium-based catalytic sys-
tem for the direct arylation reaction of 2,3,5-trisubstituted
furans and aryl halides that showed high activity with rea-
sonably broad scope was developed. The direct arylation
of 2,3,5-trisubstituted furans took place with aryl iodides
or aryl bromides to afford a range of biaryl compounds in
moderate to excellent yields in the presence of Pd(OAc)2/
Ph3P and Cs2CO3 in DMA for 20 hours.
Supporting Information for this article is available online at
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Synlett 2011, No. 10, 1472–1476 © Thieme Stuttgart · New York

1474
H. Cao et al.
LETTER
Table 2 Pd-Catalyzed Direct Arylation Reaction of Furan with Aryl Halidesa
R1
R1
Ar
Pd(OAc)2/Ph3P
Ar
X
+
DMA, Cs2CO3, 120 °C
R1
R2
R1
R2
O
O
Entry
1
Furans14,15
Aryl halides(X = I, Br)
Products16
Yield (%)b
EtO2C
Ph
R1 = CO2Et
R2 = CHO
1a
X = I, 85
X = Br, 76
X = Cl, trace
X
EtO2C
CHO
O
O
O
3a
X = I, 84
X = Br, 72
EtO2C
X
2
3
1a
1a
CHO
EtO2C
3b
EtO2C
X = I, 82
X = Br, 71
X
EtO2C
CHO
3c
Et
X = I, 83
X = Br, 70
EtO2C
4
1a
Et
X
EtO2C
CHO
O
3d
CO2Me
X = I, 90
X = Br, 80
EtO2C
5
6
1a
1a
MeO2C
X
EtO2C
CHO
CHO
O
3e
S
EtO2C
X = I, 82
X = Br, 73
X
S
EtO2C
O
3f
MeO2C
Ph
R1 = CO2Me
R2 = CHO
1b
X = I, 81
X = Br, 71
7
8
X
MeO2C
CHO
O
3g
Ph
EtO2C
R1 = CO2Et
R2 = Me
1c
X = I, 74
X = Br, 65
X
X
EtO2C
O
O
3h
EtO2C
X = I, 73
X = Br,66
9
1c
EtO2C
3i
Synlett 2011, No. 10, 1472–1476 © Thieme Stuttgart · New York

LETTER
Direct Arylation Reaction of 2,3,5-Trisubstituted Furans
1475
Table 2 Pd-Catalyzed Direct Arylation Reaction of Furan with Aryl Halidesa (continued)
R1
R1
Ar
Pd(OAc)2/Ph3P
Ar
X
+
DMA, Cs2CO3, 120 °C
R1
R2
R1
R2
O
O
Entry
Furans14,15
Aryl halides(X = I, Br)
Products16
Yield (%)b
EtO2C
X = I, 5
X = Br, 62
X
10
1c
EtO2C
O
3j
Et
X = I, 77
X = Br, 68
EtO2C
11
1c
Et
X
EtO2C
O
3k
CO2Me
X = I, 85
X = Br, 76
EtO2C
12
13
1c
1c
MeO2C
X
EtO2C
O
O
3l
S
EtO2C
X = I, 76
X = Br, 67
X
S
EtO2C
3m
OMe
X = I, 74
X = Br, 67
14
15
1c
1c
EtO2C
MeO
X
EtO2C
O
3n
EtO2C
X
X = I, 75
X = Br, 62
OMe
OMe
EtO2C
O
3o
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Acknowledgment
We thank the Teaching Foundation of Guangdong Pharmaceutical
University for financial support.
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(14) General Procedure for the Synthesis of 1a
Diethyl acetylenedicarboxylate (2 mmol), prop-2-yn-1-ol (2
mmol), DABCO (0.2 mmol) in CH2Cl2 were stirred for 10
min at r.t. And then the solution was evaporated to dryness
under reduced pressure. Subsequently, CuI (10% mmol) and
DMF were added at 80 °C. After completion of the reaction
(monitored by TLC), the solution was evaporated to dryness
under reduced pressure, and then H2O (10 mL) was added.
The aqueous solution was extracted with Et2O (3 × 10 mL),
and the combined extract was dried with anhyd MgSO4. The
solvent was removed, and the crude product was separated
by column chromatography to give a pure sample of 1a.
(15) General Procedure for the Synthesis of 1c
Diethyl acetylenedicarboxylate (2 mmol), prop-2-yn-1-ol (2
mmol), DABCO (0.2 mmol) in CH2Cl2 were stirred for 10
min at r.t. And then the solution was evaporated to dryness
under reduced pressure. Subsequently, AgOAc/Ph3P and
toluene were added at 50 °C. After completion of the
reaction (monitored by TLC), the solution was evaporated
to dryness under reduced pressure, and then H2O (10 mL)
was added. The aqueous solution was extracted with Et2O
(3 × 10 mL), and the combined extract was dried with anhyd
MgSO4. The solvent was removed, and the crude product
was separated by column chromatography to give a pure
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Cs2CO3 (1.0 mmol), 1a (0.5 mmol), 2a (0.7 mmol), and
DMP (4 mL) were added successively. The mixture was
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dried with anhyd MgSO4. Solvent was removed, and the
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Diethyl 5-Formyl-4-phenylfuran-2,3-dicarboxylate (3a)
1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1 H), 7.47 (s, 5 H),
4.43 (q, J = 8.0 Hz, 2 H), 4.28 (q, J = 8.0 Hz, 2 H), 1.40 (t,
J = 8.0 Hz, 3 H), 1.22 (q, J = 8.0 Hz, 3 H). 13C NMR (100
MHz, CDCl3): d = 178.0, 162.0, 157.1, 147.5, 144.3, 136.1,
129.7, 129.5, 128.7, 127.5, 126.3, 62.3, 62.1, 14.0, 13.7.
MS (EI): m/z (%) = 316, 288, 225, 213, 170, 115, 77.
Synlett 2011, No. 10, 1472–1476 © Thieme Stuttgart · New York