Ruthenium-catalyzed coupling reaction of 2,3,5-trisubstituted furans with aryl halides through C-H bond cleavages

Article abstract of DOI:10.1016/j.jorganchem.2011.06.009

A variety of functionalized furans were synthesized by way of a ruthenium-catalyzed coupling reaction of 2,3,5-trisubstituted furans with aryl halides through C-H bond cleavages. The feature of the reaction was facilitative preparation of furan derivative

Full text of DOI:10.1016/j.jorganchem.2011.06.009

Journal of Organometallic Chemistry 696 (2011) 3086e3090
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Journal of Organometallic Chemistry
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Ruthenium-catalyzed coupling reaction of 2,3,5-trisubstituted furans with aryl
halides through CeH bond cleavages
,
a
a
a
b
Hua Cao a , Haiying Zhan , Dongsheng Shen , Hong Zhao , Yi Liu
*
a School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
b Lab Center of Zhongshan Campus, Guandong Pharmaceutical University, Zhongshan 528458, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of functionalized furans were synthesized by way of a ruthenium-catalyzed coupling reaction of
2,3,5-trisubstituted furans with aryl halides through CeH bond cleavages. The feature of the reaction was
facilitative preparation of furan derivatives good functional group tolerance. All reactions gave the
desired products in moderate to good yields (56e89%) in the presences of [RuCl2(p-cymene)] and K2CO3
in NMP at 120 ꢀC.
Received 21 April 2011
Received in revised form
28 May 2011
Accepted 9 June 2011
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium-catalyzed
Coupling reaction
Furans
Aryl halides
1. Introduction
coupling reactions, such as Pd [32e35], Ru [36e49], and Rh
[50e53] are the most versatile and widely used metal for direct
Biaryls are important structural cores, presented in many
compounds of enormous practical importance, ranging from
pharmaceutical agents, agrochemicals, materials chemistry [1e4]
(Fig. 1). And they are also used as synthetic building blocks [5,6]
to construct a variety of substituents with diverse functional
groups natural compounds and drugs. Thus, the development of an
efficient catalytic activation system for formation of biaryls via CeH
activation is an important challenge in organic synthesis. Among
many elegant approaches, the utilization of transition metals to
form biaryls is one of the most powerful tools [7e9] and thus has
attracted great attentions [10e12].
arylation to synthesize diaryl compounds.
Furans are extremely important heterocyclic compounds
[54,55] and worth our attention because they exhibit a wide range
of biological activities [56,57]. They are not only extensively used as
communicating moieties in molecular materials, but also as
synthetic building blocks for the synthesis of more complex
compounds [58e60]. However, relatively few efforts have been
devoted to the 3-C CeH activation on furan rings probably due to its
less activity comparing to 2-C CeH bond. Therefore, the develop-
ment of new strategies and methodologies to form polyarylated
heteroarenes [61e63] remain essential. Herein, we reported
Transition-metal-catalyzed CeH activation reactions of
aromatic compounds are highly attractive research subjects in
current organic synthesis [13e28]. In this field, heterocyclic arenes
have received particular attentions as substitutes for the pre-
activated organometallic partners, which are typically used in
conventional cross-coupling reactions [29e31] and have been
extensively studied due to their structural properties. Almost all of
these arylation reactions involved electrophilic substitution at
aromatic CeH bonds or base-assisted proton abstraction from
aromatic CeH bonds. Among transition-metal-catalyzed cross-
a highly versatile Ru-catalyzed coupling reaction of 2,3,5-
trisubstituted furans with aryl halides for formation poly-
substituted furans in Scheme 1.
2. Results and discussion
Initially, we chose diethyl 5-formylfuran-2, 3-dicarboxylate 1a
and iodobenzene 2a as the starting materials and our efforts were
focused on searching for potential catalysts and suitable reaction
conditions. A series of ruthenium species were first screened for
the transformation. Inspiringly, it was found that [RuCl2(p-cym-
ene)]2 (5 mol %) displayed the highest activity to give coupling
product 3a in good yield under the following conditions: NMP
(3.0 mL), 18 h, 120 ꢀC, 1a (0.5 mmol), 2a (0.6 mmol), Ru-catalyst
* Corresponding author. Fax: þ86 760 88207839.
E-mail address: hua.cao@mail.scut.edu.cn (H. Cao).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.06.009

H. Cao et al. / Journal of Organometallic Chemistry 696 (2011) 3086e3090
3087
Table 1
Condition screening for the palladium-catalyzed direct arylation reaction of 1a with
2a.a
EtO2C
EtO2C
EtO2C
EtO2C
Ph
CHO
cat. additive
solvent
+
I
CHO
O
O
1a
2a
3a
Entry
Catalyst (mol%)a
Base
Solvent
T(ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
Ru3(CO)12
RuCl3(H2O)n
RuCl2(PPh3)3
Ru(acac)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaHCO3
KH2PO4
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
NMP
100
100
100
100
100
120
140
160
rt
120
120
120
120
120
120
120
120
120
11
35
40
13
55
74
70
51
e
Fig. 1. Biaryl motifs in bioactive molecules.
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
(5% mol), K2CO3 (1.0 mmol). Tests of other catalysts turned out to
be less effective: Ru3(CO)12, RuCl3(H2O)n, RuCl2(PPh3)3, Ru(a-
cac)2(Table 1, entries 2e4). The temperature was also tested and
indicated that 120 ꢀC was the optimal one for this transformation
(Table 1, entries 6e9). Yields became lower when the reactions
were carried out at lower temperatures. The desired coupling
product 3a was not detected, when the reaction was carried out at
room temperature after 18 h. Subsequently, the effects of bases
were tested in this coupling reaction. Among various bases
examined, 2 equiv of K2CO3 proved to be most suitable in
combination with [RuCl2(p-cymene)]2, and the usage of others
resulted in lower yields: Na2CO3, Cs2CO3, NaHCO3, KH2PO4, KOAc
(Table 1, entries 10e14). Next, the effects of solvent were exam-
ined, it was found other solvents, such as toluene, DMSO, DMA
and DMF could afford the products as well, albeit in lower yield
(Table 1, entries 15e18).
9
10
11
12
13
14
15
16
17
18
62
66
35
29
34
46
50
87
63
DMA
a
Reaction condition:1a (0.5 mmol) and 2a (0.6 mmol), Ru-catalyst (5% mol),
K2CO3 (1.0 mmol), solvent (3 mL), 18 h.
b
GC yields.
the CeH bond cleavage by proton abstraction and generates a five-
membered ruthenacycle, which was further stabilized by coordi-
nation of ortho-carbonyl group (Scheme 2, see B); Alternatively,
a similar pathway involving aldehyde directed proton abstraction
(Scheme 2, see A’) could also give intermediate B; B was expected
to undergo reversibly oxidative addition of aryl halide and results in
a Ru(IV) species C; Finally, the expected coupling product was
released from C via reductive elimination and Ru(II) catalyst was
regenerated.
With the optimized conditions in hand (Table 1, entry 17), we
next turned our attention to the scope of the coupling reaction. As
shown in Table 2, under the optimized conditions, the coupling
reaction of 2,3,5-trisubstituted furans were readily achieved with
a variety of substituted aryl halides (X ¼ I, Br). The reaction was
potential to be broadly applicability. From Table 2, the reaction
conditions had proven to be useful for
a range of 2,3,5-
trisubstituted furans 1ae1c. Also, the reaction of 1ae1c with
differently substituted aryl iodides (Ar ¼ Phe, 4-CH3Phe, 2-
CH3Phe, 4-EtPhe, 4-CH3OPhe,2-CH3OPhe, 2-thienyl, 4-
CH3O2CPhe) had a beneficial effect on the reaction outcomes,
and in most cases the corresponding products were obtained in
moderate to good yields (Table 2, entries 7e17) under our standard
experimental conditions. Interestingly, it was also found that not
only a variety of substituted aryl iodides but also aryl bromides
derivatives were given in moderate to good yields in the presence
of [RuCl2(p-cymene)]2. These results indicated that this coupling
reaction tolerated functional groups on aromatic ring. There was no
effect for this transformation with either the electron-rich or
electron-withdrawing groups at the aromatic ring.
4. Conclusions
In summary, we had established an efficient, direct arylation
and ruthenium-catalyzed CeC bonds formation method to
construct the biaryl compounds. The current protocol can find
potential use in various fields.
5. Experimental section
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, with TMS as the internal standard. IR spectra were
obtained either as potassium bromide pellets or as liquid films
between two potassium bromide pellets with a Bruker Vector 22
spectrometer. TLC was performed by using commercially prepared
100e400 mesh silica gel plates (GF254) and visualization was
effected at 254 nm. All the other chemicals were purchased from
Aldrich Chemicals.
3. Mechanism
As mentioned in similar studies [36,64e66], a plausible mech-
anism of this Ru-catalyzed direct CeH arylation was depicted as
follows (Scheme 2): The ester group serves as a directing group to
form transitional precursor A, the presence of base could promote
Typical Experimental Procedure for the Synthesis of 3a: To the
mixture of [RuCl2(p-cymene)]2 (0.05 equiv), K2CO3 (2 equiv), 1a
(1 equiv), 2a (1.5 equiv) and 3 mL NMP were added successively.
The mixture was stirred at 120 ꢀC for 18 h. The solution was
extracted with ethyl acetate (3 ꢁ 15 mL), and the combined extract
was dried with anhydrous MgSO4. Solvent was removed, and the
residue was separated by column chromatography to give the pure
sample 3a.
Scheme 1. Ru-catalyzed coupling reaction.

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H. Cao et al. / Journal of Organometallic Chemistry 696 (2011) 3086e3090
Table 2
Pd-catalyzed direct arylation reaction of
a
-carbonyl furan furan with aryl halides.a
R1
R1
Ar
R2
[RuCl2(p-cymene)]2
NMP, K2CO3, 120oC
+
Ar
X
R1
R2
R1
O
1a-1c
O
2
3a-3p
Entry
1
Substituted Furan
ArX
Product
Yield (%)b
EtO2C
Ph
1a
X ¼ I, 84
R1 ¼ CO2Et;
Ph
X ¼ Br, 71
R2 ¼ CHO
EtO2C
CHO
CHO
O
3a
EtO2C
EtO2C
X ¼ I, 87
2
3
4
5
1a
1a
1a
1a
3-MePh
2-MePh
4-EtPh
X ¼ Br,76
O
3b
EtO2C
EtO2C
X ¼ I, 80
X ¼ Br, 70
CHO
Et
O
3c
X ¼ I, 83
EtO2C
EtO2C
X ¼ Br, 70
CHO
O
3d
CO2Me
X ¼ I, 89
EtO2C
EtO2C
4-MeCOPh
X ¼ Br, 80
CHO
CHO
O
3e
S
EtO2C
EtO2C
6
7
1a
1a
2-thienyl
2-MeOPh
X ¼ I, 78
X ¼ Br, 70
O
3f
EtO2C
EtO2C
X ¼ I, 86
OCH3
X ¼ Br, 75
CHO
O
3g
EtO2C
EtO2C
1b
X ¼ I, 81
8
R1 ¼ CO2Et;
Ph
X ¼ Br, 71
O
R2 ¼ C3H7CO
O
C3H7
3h
Ph
EtO2C
EtO2C
1c
X ¼ I, 81
9
R1 ¼ CO2Et;
Ph
X ¼ Br,70
R2 ¼ CH3
O
3i

H. Cao et al. / Journal of Organometallic Chemistry 696 (2011) 3086e3090
3089
Table 2 (continued )
Entry
Substituted Furan
ArX
Product
Yield (%)b
EtO2C
EtO2C
X ¼ I 80
10
1c
3-MePh
X ¼ Br, 75
O
3j
EtO2C
EtO2C
X ¼ I, 71
11
1c
2-MePh
X ¼ Br, 56
O
3k
Et
X ¼ I, 77
EtO2C
EtO2C
12
1c
4-EtPh
X ¼ Br, 61
O
3l
CO2CH3
X ¼ I, 90
EtO2C
EtO2C
13
14
15
1c
1c
1c
Ph
X ¼ Br, 81
O
3m
S
EtO2C
EtO2C
X ¼ I, 76
2-thienyl
X ¼ Br, 70
O
3n
EtO2C
EtO2C
X ¼ I, 86
2-MeOPh
OCH3
OCH3
X ¼ Br, 71
O
3o
X ¼ I, 85
X ¼ Br, 72
EtO2C
EtO2C
16
1c
4-MeOPh
O
3p
a
Reactions condition:1a (1 equiv) and 2a (1.5 equive), Ru-catalyst (0.05 equiv), K2CO3 (2.0 equiv), solvent (3 mL), 18 h, 120 ꢀC.
Isolated yields.
b

3090
H. Cao et al. / Journal of Organometallic Chemistry 696 (2011) 3086e3090
Scheme 2. Plausible reaction mechanism.
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