An efficient and general iron-catalyzed one-pot synthesis of furans via α-hydroxy ketones and activated alkynes

Article abstract of DOI:10.1002/ejoc.201200163

A new practical and economical process for the synthesis of substituted furan derivatives has been developed by an FeCl₃-catalyzed reaction of α-hydroxy ketones with activated alkynes. This methodology represents a highly efficient synthetic route to electron-deficient furans for which catalytic approaches are scarce. Furthermore, this transformation is associated with readily available substrates, good yields, and mild conditions. An efficient iron-catalyzed one-pot synthesis of polysubstituted furans has been developed from electron-deficient alkynes and α-hydroxy ketones under mild reaction conditions. This green and eco-friendly system has shown high catalytic activity in the synthesis of furan derivatives. The yields are good, and the scope of substrates is wide.

Full text of DOI:10.1002/ejoc.201200163

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200163
An Efficient and General Iron-Catalyzed One-Pot Synthesis of Furans via
α-Hydroxy Ketones and Activated Alkynes
Hua Cao,*[a] Haiying Zhan,[a] Jianyong Wu,[a] Haiping Zhong,[a] Yuanguang Lin,[a] and
Hong Zhang[a]
Keywords: Alkynes / Furans / α-Hydroxy ketones / Iron / Oxygen heterocycles
A new practical and economical process for the synthesis of
substituted furan derivatives has been developed by an
FeCl3-catalyzed reaction of α-hydroxy ketones with activated
alkynes. This methodology represents a highly efficient syn-
thetic route to electron-deficient furans for which catalytic
approaches are scarce. Furthermore, this transformation is
associated with readily available substrates, good yields, and
mild conditions.
furan derivatives, we have designed and developed a new
efficient one-pot protocol for the construction of furans. In
this paper, we described a facile iron-catalyzed strategy to
prepare the furan derivatives from electron-deficient al-
kynes and α-hydroxy ketones.
Introduction
Furans are a fundamental class of five-membered hetero-
cycles, which have been found as key structural units in
many natural products.[1]They are not only prevalent in an
extensive variety of biologically and medicinally important
molecules,[2] but also used as a building blocks in organic
synthesis.[3] These advantages have prompted a search for
better methods to synthesize furans. Generally, there are
mainly two routes to construct furan derivatives:[4] (i) cycli-
zation of allenyl ketones,[5] alkynyl ketones,[5d,6] enyn-
Results and Discussion
The intermediate product of dimethyl 2-(1-methyl-2-oxo-
ols,[5d,7] alkynyl epoxides[8] or propargyl ethers;[9] (ii) cycli- propoxy)maleate (3) was easily prepared through nucleo-
zation of 1,4-dicarbonyl compounds (Paal–Knorr synthe- philic addition of dimethyl but-2-ynedioate (1a) with 3-hy-
sis). Although a number of synthetic methods for the prepa- droxybutan-2-one (2a) in the presence of DABCO. A typi-
ration of substituted furans have been reported, it is essen- cal procedure is: 1a (0.5 mmol), 2a (0.5 mmol) and DABCO
tial to develop new strategies for the synthesis of furans in CH2Cl2 were stirred at room temperature. Then the solu-
under much milder conditions and the use of simpler cata- tion was concentrated to dryness under reduced pressure.
lytic systems.
Subsequently, a variety of iron catalysts were examined at
Iron is one of the cheapest and most abundant metals on 90 °C, and the results are summarized in Table 1. Initially,
earth.[10] Despite its advantages, it is surprising that iron we examined the reaction in the presence of 10 mol-%
plays a diminutive role in the field of catalysis[11] compared FeCl3·6H2O (entry 1). We were pleased to observe that the
to other transition metals such as palladium and rhodium. reaction proceeded smoothly in 8 h to afford exclusively 3aa
Therefore, the development of a more practical Fe-cata- in 34% yield (Table 1, Entry 1). Other iron catalysts, such
lyzed system that can be used to prepare complex and di- as Fe(ClO4)3·xH2O, Fe(acac)3, Fe(NO3)3·9H2O, Fe2(SO4)3·
verse heterocyclic compounds under mild conditions is de- xH2O, Fe(DBM)3, Fe2O3, FeCl2 (Entries 2–8), were also ex-
sired.
amined in this reaction, but the yields of product 3aa
Very recently, our group reported convenient one-pot dropped sharply. Interestingly, it was found that the desired
domino processes for the synthesis of highly functionalized product 3aa was obtained in 66% yield, when CH3CO2H
polysubstituted furan derivatives through different transi- was added to the reaction mixture. The results encouraged
tion-metal-catalyzed cyclizations.[12] To extend the scope of us to check other additives, such as PhCO2H, F3CO2H,
HCl, TsOH, l-proline (Entries 10–14), but they led to lower
[a] School of Chemistry and Chemical Engineering, Guangdong
yields of product 3aa. In most of these cases, only traces of
the product were found by TLC, and most of the intermedi-
ate 3 had disappeared (Table 1, Entries 11–13). To our de-
light, there was a significant difference with the addition
of FeCl3, because the corresponding product 3aa was not
detected without the presence of FeCl3 during the reaction
Pharmaceutical University,
Guangzhou 510006, P. R. of China
Fax: +86-760-88207939
E-mail: hua.cao@mail.scut.edu.cn
nancyzhy@foxmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200163.
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Iron-Catalyzed One-Pot Synthesis of Furans
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Additive
Solvent
T [°C]
t [h]
Yield [%][b]
1[c]
2
FeCl3·6H2O (Ͼ98%)
FeClO4·xH2O (Ͼ98%)
Fe(acac)3 (Ͼ98%)
Fe(NO3)3·9H2O (Ͼ99%)
Fe2(SO4)3·xH2O (Ͼ97%)
Fe(DBM)3 (Ͼ98%)
Fe2O3 (Ͼ98%)
FeCl2 (Ͼ99%)
FeCl3·6H2O
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
DCE
1,4-dioxane
toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
60
40
120
r.t.
60
60
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
34
26
11
16
25
10
22
–
66
46
trace
–
3[d]
4
5
6[e]
7
8
9
CH3CO2H
PhCO2H
F3CO2H
HCl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29[f]
30[g]
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
TsOH
–
40
–
FeCl3·6H2O
l-proline
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
–
AlCl3
ZnCl2
Yb(OTf)3
Sc(OTf)3
55
63
50
11
73
49
38
53
65
85
77
61
–
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O/CuCl2
FeCl3·6H2O/CuCl
82
36
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 10 mol-% of catalysts and 5 mol-% of DABCO, 10 mol-% of additives in 2 mL of
solvent at room temp. to 120 °C for 8 h. [b] Yield determined by GC. [c] Ͻ 5 ppm Cu (Aldrich). [d] acac = pentane-2,4-dione. [e] DBM
= dibenzoyl methane. [f] 100 ppm CuCl2. [g] 100 ppm CuCl.
(Table 1, Entry 15). Other catalyst, such as AlCl3, ZnCl2
With optimal reaction conditions in hand, we explored
Yb(OTf)3 and Sc(OTf)3, were also tested, and it was found the scope of this FeCl3-catalyzed reaction, and the results
that FeCl3 was the best one (Table 1, Entries 16–19). Sol- are outlined in Table 2. By using 1a as a fixed substrate, we
vent effects were also investigated. It was found that com- carried out the reactions with various types of α-hydroxy
pound 3aa could be obtained in 73% yield in CH3CN ketones bearing aromatic and aliphatic substituted. In all
(Table 1, Entry 20), but when 1,2-dichloroethane (DCE), these cases we found that the corresponding products could
1,4-dioxane, toluene or DMF were employed, the reaction be obtained in good yields (Entries 1–8). These results indi-
was severely retarded (Table 1, Entries 11–24). Finally, we cated that the reaction conditions are compatible with a
examined the effect of temperature (Entries 25–28), and the number of functional groups in the α-hydroxy ketones.
results show that the optimal temperature is 60 °C.
When diethyl but-2-ynedioate (1b) was examined as a sub-
To eliminate the influence of active copper traces from strate, the desired furans were obtained in good yields
iron salts in this transformation, FeCl3 was analyzed by (Table 2, Entries 10–17).
ICP, yielding a content of only Ͻ 5 ppm Cu. Further in-
We next evaluated the scope of this transformation with
vestigations of the influences of copper salts on the reaction respect to using 2a as a fixed substrate. Other electron-de-
had been carried out. FeCl3 with CuCl2 or CuCl (100 ppm) ficient alkynes, such as ethyl but-2-ynoate (1c), ethyl 3-
were employed as cocatalysts, and the product was obtained phenylpropiolate (1d) and 1,3-diphenylprop-2-yn-1-one
in 82% and 36% yield, respectively (Table 1, Entries 29, 30). (1e), were checked. To our delight the corresponding furan
These results clearly indicate that the Fe catalyst plays a derivatives were obtained in moderate to good yields
crucial role in this transformation.
(Table 2, Entries 18–20). All these cases clearly indicate that
Eur. J. Org. Chem. 2012, 2318–2322
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H. Cao, H. Zhan, J. Wu, H. Zhong, Y. Lin, H. Zhang
Table 2. (Continued)
SHORT COMMUNICATION
Table 2. Substrate scope for the synthesis of furan derivatives.[a]
>
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 10 mol-% of
FeCl3 and 5 mol-% of DABCO, 10 mol-% of CH3OOH in 2 mL of
CH3CN at 60 °C for 8 h. [b] Isolated yields. [c] PBu3 substituted
DABCO as a catalyst.
the reaction condition both bear various types of electron-
deficient alkynes and α-hydroxy ketones. Unfortunately, the
desired product and intermediate were not detected during
the reaction, when non-activated diphenylacetylene (1f) was
tested as the substrate (Table 2, Entry 21).
A plausible mechanism accounting for the cycloaddition
process is depicted in Scheme 1. DABCO-promoted nu-
cleoaddition of an α-hydroxy ketones to an electron-de-
ficient alkyne forms adduct A, which is activated by FeCl3
and H+ to generate B. The coordination of H+ to the carb-
onyl group lowers the electron density of the carbon–oxy-
gen double bond, which makes the nucleophilic attack of
the α-carbon atom toward the carbonyl carbon atom pos-
sible to form intermediate C. Finally, intermediate C un-
dergoes sequential dehydration and deprotonation to give 3
as the desired product.
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Iron-Catalyzed One-Pot Synthesis of Furans
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[3]
[4]
Scheme 1. Working mechanism for the cycloaddition process.
[5]
Conclusions
This paper described the FeCl3-catalyzed one pot cyclo-
addition of α-hydroxy ketones to activated alkynes. The re-
action provides a convergent approach to generate a C–C
and a C–O bond for the synthesis of furan derivatives in
moderate to good yields. Further studies will be focused
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SHORT COMMUNICATION
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Received: February 11, 2012
Published Online: March 15, 2012
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