Iron-catalyzed domino process for the synthesis of α-carbonyl furan derivatives via one-pot cyclization reaction

Article abstract of DOI:10.1021/jo100813w

(Figure presented) The Fe(ClO₄)₃-catalyzed intramolecular rearrangement/cyclization/oxidation reaction sequence for the synthesis of α-carbonyl furan derivatives from electron-deficient alkynes and 2-yn-1-ols is reported.

Full text of DOI:10.1021/jo100813w

pubs.acs.org/joc
effective properties. Over the past decades, iron catalysts
Iron-Catalyzed Domino Process for the Synthesis of
r-Carbonyl Furan Derivatives via One-Pot
Cyclization Reaction
have been extensively applied to various reactions, such as
oxidation,5 epoxidation,6 addition,7 cyclization,8 etc. However,
the iron-catalyzed C-C and C-O bond-forming reactions
are underdeveloped and have become a long-term goal for
synthetic chemists in modern organic synthesis.
Herein, we report a Fe(ClO4)3-catalyzed domino reaction
for the synthesis of R-carbonyl furan derivatives from elec-
tron-deficient alkynes and 2-yn-1-ols. Furans exhibit parti-
cularly valuable and rich chemistry and extensive biological
activity,9 are useful as synthetic building blocks,10 and are
contained in many natural products.11 Over the past dec-
ades, several methodologies for the construction of furan
skeletons have been developed with Cu, Pd, Rh, Au, and Ag
catalytic systems.12,13 Those methodologies are convenient
Huanfeng Jiang,* Wenjuan Yao, Hua Cao, Huawen Huang,
and Derong Cao
School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received April 26, 2010
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The Fe(ClO4)3-catalyzed intramolecular rearrangement/
cyclization/oxidation reaction sequence for the synthesis
of R-carbonyl furan derivatives from electron-deficient
alkynes and 2-yn-1-ols is reported.
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DOI: 10.1021/jo100813w
r
Published on Web 06/30/2010
J. Org. Chem. 2010, 75, 5347–5350 5347
2010 American Chemical Society

Jiang et al.
JOCNote
TABLE 1. Optimization of Reaction Conditions
SCHEME 1. Iron-Catalyzed Synthesis of r-Carbonyl-β-yne
Furans
yield
T (°C) (%)a
entry
catalyst
solvent
1
2
3
Fe(acac)3 (>98%)
FeCl3 (>98%)
DMF
DMF
DMF
80
80
80
23
35
72
Fe(ClO4)3 xH2Ob
(>98%)
3
4
5
Fe(NO3)3 9H2O (>99%) DMF
3
80
80
18
20
Fe2(SO4)3 xH2O
3
DMF
(>97%)
6
7
8
9
10
11
12
13
14
15
16
17
18
FeCl2 (>99%)
Fe(C5H5)2 (>99%)
Fe powder (>99%)
DMF
DMF
DMF
DMF
toluene
benzene
1,2-dichloroethane
1,4-dioxane
CH3CN
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
80
80
100
50
rt
Fe(ClO4)3 xH2O
3
<5
<5
47
54
58
80
76
71
Fe(ClO4)3 xH2O
3
Fe(ClO4)3 xH2O
Fe(ClO4)3 xH2O
3
3
Fe(ClO4)3 xH2O
Fe(ClO4)3 xH2O
3
3
Fe(ClO4)3 xH2O
Fe(ClO4)3 xH2O
3
variety of iron catalysts (20 mol %) in DMF were added to
the residue at 80 °C. The mixture was stirred until completion
of the reaction (monitored by TLC). As shown in Table 1, the
reaction could be catalyzed by FeIII salts, such as Fe(acac)3,
FeCl3, Fe(ClO4)3 xH2O, Fe(NO3)3 9H2O, and Fe2(SO4)3
3
Fe(ClO4)3 xH2O
DMSO
DMSO
DMSO
3
19c Fe(ClO4)3 xH2O/CuI
80
80
27
38
3
20d Fe(ClO4)3 xH2O/CuBr2
3
aYield determined by GC. bCaution! Metal perchlorate salts can
be explosive. 20 mol % Fe(ClO4)3 xH2O, 100 ppm CuI. d20 mol %
Fe(ClO4)3 xH2O, 100 ppm CuBr2.
3
c
3
3
3
3
xH2O (Table 1, entries 1-5). Fe(ClO4)3 xH2O was the most
3
effective catalyst (Table 1, entry 3). The product 4aa was not
detected in the presence of FeII salts, Fe0, or catalyst-free
conditions (Table 1, entries 6-9), and 3aa was obtained as
the sole product. In addition, we tried to improve the yields
by using various solvents. Among the solvents surveyed, low
yields (<5%) of product 4aa were found in toluene and
benzene (Table 1, entries 10 and 11). However, higher yields
of 3aa were obtained in 1,2-dichloroethane, 1,4-dioxane,
CH3CN, and DMSO (Table 1, entries 12-15). DMSO was
the most effective media for this domino reaction. The opti-
mization of reaction temperature showed that 80 °C was
optimal (Table 1, entries 16-18).
with good yields. However, reports on the synthesis of R-
carbonyl furans are relatively rare.14 During our ongoing
research to explore expedient routes to these types of com-
pounds, we were delighted to find that iron could be a good
catalyst for the construction of furans.
We recently developed a one-pot CuI-catalyzed domino
process to synthesize functionalized furans.15 Unfortunately,
this domino reaction did not take place when 1,3-diphenyl-
prop-2-yn-1-one was employed as the substrate instead of
diethyl but-2-ynedioate. Inspired by our recent advances on
oxygen-mediated transformations,16 we developed a method
for furan formation with iron salts as catalysts. The method
is a facile alternative to the synthesis of highly functionalized
R-carbonyl furans from electron-deficient alkynes and 2-yn-
1-ol in a one-pot manner.
In order to exclude the possibility that trace copper in iron
salts might affect the reaction,19 Fe(ClO4)3 xH2O was ana-
3
lyzed by ICP. The analysis showed that the amount of Cu
was below 5 ppm in the sample. Further experiments indi-
cated the detrimental influence of copper salts. When a
On the basis of our previous work and assumption,15,17 we
tried to find the best iron catalysts and optimize our reaction
conditions by using 1a and 2a as the starting materials. In a
typical procedure, a solution of 1a (0.5 mmol), 2a (0.5 mmol),
and PBu3 in CH2Cl2 was stirred at room temperature.18 The
solvent was evaporated under reduced pressure. Then a
mixture of Fe(ClO4)3 xH2O with CuI or CuBr2 was used
3
as catalysts, the yields of 4aa were only 27% and 38%,
respectively (Table 1, entries 19 and 20). The results con-
formed that Fe played a crucial role in this intramolecular
rearrangement/cyclization/oxidation reaction.
In order to explore the scope of this reaction, various
electron-deficient alkynes and 2-yn-1-ols were evaluated at
ꢀ
(14) Barluenga, J.; Riesgo, L.; Vicente, R.; Lopez, L. A.; Tomas, M. J.
ꢀ
80 °C with 20 mol % of Fe(ClO4)3 xH2O as the catalyst, and
3
Am. Chem. Soc. 2008, 130, 13528.
(15) Cao, H.; Jiang, H. F.; Yao, W. J.; Liu, X. H. Org. Lett. 2009, 11,
1931.
(16) (a) Wang, A. Z; Jiang, H. F. J. Am. Chem. Soc. 2008, 130, 5030.
(b) Wang, A. Z; Jiang, H. F; Chen, H. J J. Am. Chem. Soc. 2009, 131, 3846.
(17) Cao, H.; Jiang, H. F.; Mai, R. H.; Zhu, S. F.; Qi, C. R. Adv. Synth.
Catal. 2010, 352, 143.
DMSO as solvent. The results are summarized in Table 2.
The electron-deficient alkynes such as 1a-d reacted well with
alkynyl alcohols 2a-c (Table 2, entries 1-9, 13-15). Diff-
erent substituted 2-yn-1-ols, such as 2-thienyl, 3-nitrophenyl,
(18) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(19) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586.
5348 J. Org. Chem. Vol. 75, No. 15, 2010

Jiang et al.
JOCNote
TABLE 2. Iron-Catalyzed Synthesis of r-Carbonyl Furans
a1d (0.5 mmol), 2 (0.5 mmol) and DABCO in CH2Cl2 were stirred at room temperature to afford the product propargyl vinyl ether.
m-tolyl, 3-methoxyphenyl, and 2-pyridyl led to a beneficial
effect on the reaction outcome, and in most cases the corres-
ponding products (4ca-cf) were obtained in good yields
(49-83%) (Table 2, entries 7-13). These results demon-
strate that the domino process could occur with functional
groups at different positions of the aromatic ring. It is worthy
to note that the corresponding furans and all of the desired
products were formed with high regioselectivity. In addition,
R-carbonyl-β-yne furans were isolated in moderate yields
when 2,4-diyn-1-ols were used (Scheme 1).
Subsequenly, a 6-endo-dig addition of the enol ether onto the
iron(III)-alkyne complex resulted in the formation of six-
membered intermediate B, which collapsed into the β-allenic
ketone C.13h,15 Finally, β-allenic ketone underwent sequen-
tial cyclization, carbene-oxidation, and dehydration-oxida-
tion to form furan 4.
In summary, we have described an iron-catalyzed domino
reaction for the synthesis of R-carbonyl furans from easily
available starting materials in DMSO at 80 °C under atmo-
spheric pressure. It could be expected that this new synthetic
method will be applied widely in organic synthesis because R-
carbonyl furans are extremely useful organic molecules as
synthetic building blocks for the synthesis of elaborate
heterocyclic compounds.
A plausible reaction mechanism for iron-catalyzed synth-
esis of furans is described in Scheme 2. First, DABCO- or
PBu3-promoted nucleophilic addition of propargyl alcohol
(2) to electron-deficient alkyne (1) afforded enyne adduct 3.
J. Org. Chem. Vol. 75, No. 15, 2010 5349

Jiang et al.
JOCNote
SCHEME 2. Plausible Mechanism
1a (103 mg, 0.5 mmol), prop-2-yn-1-ol 2a (28 mg, 0.5 mmol),
and PBu3 (0.1 mmol) in CH2Cl2 was stirred for 30 min at room
temperature. The solvent was evaporated under reduced
pressure. Fe(ClO4)3 and DMSO were added at 80 °C under
atmospheric pressure. After completion of the reaction
(monitored by TLC), the solvent was evaporated under re-
duced pressure. Water (8 mL) was added, and the aqueous
solution was extracted with diethyl ether (3 Â 8 mL). The
combined extracts were dried with anhydrous MgSO4. The
solvent was removed, and the crude product was separated by
column chromatography to give pure 4aa (101 mg, 73%). IR
(KBr): 3028, 2834, 1650, 1602, 763. 1H NMR (CDCl3, 400
MHz): δ 9.70 (s, 1H), 7.78-7.83 (m, 4H), 7.53-7.57 (m, 1H),
7.32-7.44 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 190.4,
177.5, 159.8, 150.3, 137.0, 133.6, 130.7, 129.7, 128.7,128.6,
128.2, 128.1, 123.7, 122.7. HRMS (EI): calcd for C18H12O3
276.0786, found 276.0780.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (Nos. 20625205, 20772034,
and 20932002) and Doctoral Fund of Ministry of Education
of China (20090172110014).
Experimental Section
Supporting Information Available: Compound characteri-
zation data. This material is available free of charge via the
Internet at http://pubs.acs.org.
GeneralProcedureforthe Synthesisof4-Benzoyl-5-phenylfuran-
2-carbaldehyde (4aa). A solution of 1,3-diphenylprop-2-yn-1-one
5350 J. Org. Chem. Vol. 75, No. 15, 2010