Synthesis of 4H-cyclopenta[c]furans via cooperative PdCl 2-FeCl2 catalyzed cascade cyclization reaction involving a novel acyl rearrangement process

Article abstract of DOI:10.1039/c2cc31138k

We have discovered a novel PdCl₂-FeCl₂ catalyzed cascade cyclization reaction, which involves a novel acyl rearrangement process. This reaction affords a diverse set of poly-substituted 4H-cyclopenta[c]furan products. The reaction sc

Full text of DOI:10.1039/c2cc31138k

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Synthesis of 4H-cyclopenta[c]furans via cooperative PdCl2–FeCl2
catalyzed cascade cyclization reaction involving a novel acyl
rearrangement processw
Huanfeng Jiang,* Xiaoyan Pan, Liangbin Huang, Jian Zhao and Dabin Shi
Received 15th February 2012, Accepted 15th March 2012
DOI: 10.1039/c2cc31138k
We have discovered a novel PdCl2–FeCl2 catalyzed cascade
cyclization reaction, which involves a novel acyl rearrangement
process. This reaction affords a diverse set of poly-substituted
4H-cyclopenta[c]furan products. The reaction scope of this
cascade process is quite broad and various internal acetylenes
can be employed.
Table 1 PdCl2-catalyzed cyclization of 2-yn-1-one (1) to multi-
substituted 4H-cyclopenta[c]furan (2)a
Transition metal catalyzed cascade cyclization processes are
fascinating strategies in the synthesis of natural products and
biologically-active agents, because multiple bonds can be
formed in a single transformation with exceptional selectivity.1
However, dual-metal catalysis has attracted much attention.2
Palladium catalyzed cascade reactions have been demonstrated
to be versatile tools for the synthesis of numerous polycyclic
compounds, and cooperative catalysts like copper complexes
have been employed to enhance the reaction efficiency and
selectivity.3 However, synthetic methodologies employing
homogeneous cooperative palladium and iron catalysts are
fairly rare, even though iron catalysis is being exhaustively
investigated.4,6d Herein, we wish to report a novel synthesis of
4H-cyclopenta[c]furans via cooperative PdCl2–FeCl2 catalyzed
cascade cyclization reaction. This chemistry presumably goes
through two consecutive processes, the palladium-catalyzed
cycloaddition and the iron-catalyzed acyl rearrangement.
Recently, palladium-catalyzed cycloaddition reactions of
alkynes have emerged as a privileged approach for the rapid
construction of cyclic rings.5 For instance, we and others have
reported a number of unique palladium-catalyzed cyclization
and cyclotrimerization reactions employing commonly avail-
able acetylenes to afford diverse heterocyclic and carbocyclic
compounds.6 4H-Cyclopenta[c]furan derivatives possess interesting
molecular skeletons and electronic features, which should
exhibit remarkable biological and physical properties. However,
the state of art synthetic methodology is far behind satisfactory,
posing an obstacle to the investigation of its potential applications.
Entry
Alkynone
R1
R2
Product
Yieldb [%]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
70
65
60
61
68
67
4-CH3C6H4
2-MeOC6H4
4-BrC6H4
4-FC6H4
Me
a
Reaction conditions: substrate 1 (1 mmol), PdCl2 (0.1 mmol), FeCl2
(0.05 mmol), LiCl (2 equiv.) in 3.0 mL of xylene at 80 1C under an
atmosphere of 1 atm N2 for 24 h. Yield of isolated products.
b
One viable approach to synthesize 4H-cyclopenta[c]furans
could be transition metal catalyzed cycloaddition reaction of
acetylenes bearing oxygen-containing functionalities, like
2-yn-1-one derivatives.7
To test this hypothesis, 1,3-diphenyl-propynone was treated
with PdCl2 (10 mol%) and LiCl (2 equiv.) in xylene (3.0 mL) at
80 1C under 1 atm N2 for 24 h. To our delight, a small amount
of cyclopenta[c]furan product was formed and isolated by
flash chromatography (ESIw; Table 1, entry 2). The structure
of this compound was subsequently determined by NMR and
X-ray crystallography analyses of 2a and 2k (Fig. 1). Further
study indicated that 47% yield of the product 2a was obtained
while an additional catalyst Cu(OTf)2 was employed. Encouraged
by these results, a diverse set of cooperative metal catalysts
were screened and FeCl2 appears to be the most suitable one.
Surprisingly, a moderate yield can also be achieved when this
reaction is conducted in the presence of a strong Brønsted acid
HCl. In order to understand the intrinsic role of the FeCl2
catalyst, this reaction was performed in the absence of PdCl2,
and no desired product was obtained. Finally, this reaction
was carried out in air and oxygen. Interestingly, a much lower
yield was obtained when this reaction was conducted in the
presence of oxygen. These results indicate that this chemistry
School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, China.
E-mail: jianghf@scut.edu.cn; Fax: +862087112906;
Tel: +862087112906
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for isolated compounds. See DOI: 10.1039/c2cc31138k
c
4698 Chem. Commun., 2012, 48, 4698–4700
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Fig. 1 X-Ray molecular structures of 2a and 2k.
should be a palladium(0)-mediated reaction, yet we cannot
rule out other possibilities since the overall reaction mechanism
is still under investigation (for information on the optimization
of 2a, see ESIw).
With the ‘‘optimal’’ reaction conditions in hand, we sub-
sequently explored the reaction scope. First, we examined the
steric and electronic effects of the aryl substituents adjacent to
the carbonyl group of the acetylenes, as shown in Table 1. It
appears that the reaction yields were slightly lower when
electron-donating or electron-withdrawing group substituted
2-yn-1-ones were employed (entries 2–5), possibly suggesting
that the catalytic cycles involved have distinct preference over
the electronic nature of the acetylenes.
Scheme 1 Proposed mechanism.
To understand the effect of the substituent adjacent to the
triple bond, acetylenes in which R1 is aryl or alkyl group were
employed in this transformation (Table 2). It appears that
both electron-donating and electron-withdrawing group sub-
stituted aryl acetylenes afforded respectable yields of the
desired products (entries 1–5). In addition, when alkyl sub-
stituted alkyne 1l was allowed to react under the ‘‘optimal’’
conditions, a 65% yield of the desired product was obtained.
Acetylenes lacking aromatic rings like compound 1m were
employed in this chemistry (Table 2, entry 7). To our delight,
the cascade cyclization reaction of 1m gave 68% yield of the
desired product 2m after purification.
of 4H-cyclopenta[c]furans bearing both alkyl and aryl groups
with different electronic characters. In addition, quaternary
carbon centers can be constructed at the 4 position of the
cyclopenta[c]furan ring by using internal acetylenes.
A proposed mechanism of this unprecedented PdCl2–FeCl2
catalyzed cascade cyclization reaction is illustrated in Scheme 1.
This chemistry presumably goes through two consecutive
processes, the palladium-catalyzed cycloaddition and the
iron-catalyzed acyl rearrangement. Allene intermediate A0,8
generated from the Pd(0)9-catalyzed isomerization of acetylene
A, undergoes nucleophilic addition to another acetylene A to
produce intermediate B. This addition process could possibly
be assisted by the FeCl2 co-catalysts, which may serve to
stabilize the intermediates involved. The palladium complex
B subsequently undergoes an intramolecular cyclization to
afford a palladium carbene intermediate C.10 Another molecule
of A could react with intermediate C to afford palladium carbene
intermediate D.11 At this stage, intermediate D could either
undergo a direct carbene insertion reaction to afford the final
product 2 (path b), or it could react with the Lewis acid
co-catalyst to generate intermediate E (path a),12 which rapidly
goes through an unprecedented rearrangement process to afford
intermediate G and release the Fe co-catalyst. Subsequent
reductive elimination of intermediate G should afford the
4H-cyclopenta[c]furan products. Given the fact that Brønsted
acids or Lewis acids are essential for the success of this chemistry,
a mechanism going through path b appears to be more likely.
In conclusion, we have discovered a novel PdCl2–FeCl2
catalyzed cascade cyclization reaction, which affords a diverse
set of poly-substituted 4H-cyclopenta[c]furan products. The
reaction scope of this cascade process is quite broad and
various internal acetylenes can be employed. This reaction
appears to involve two consecutive processes, the palladium-
catalyzed cycloaddition and the iron-catalyzed acyl rearrange-
ment. However, the exact reaction mechanism has not been
These results demonstrated that the cascade reaction
developed by us has broad scope and can afford a diverse set
Table 2 PdCl2-catalyzed cyclization of 2-yn-1-one (1) to multi-
substituted 4H-cyclopenta[c]furan (2)a
Entry Alkynone R1
R2
Product Yieldb [%]
1
2
3
4
5
6
7
1g
1h
1i
1j
1k
1l
4-MeOC6H4 Ph
2g
2h
58
51
57
68
69
65
68
4-t-BuC6H4
4-CH3C6H4
2-FC6H4
3-FC6H4
n-Hexyl
Et
Ph
4-FC6H4 2i
Ph
Ph
Ph
Me
2j
2k
2l
1m
2m
a
Reaction conditions: substrate 1 (1 mmol), PdCl2 (0.1 mmol), FeCl2
(0.05 mmol), LiCl (2 equiv.) in 3.0 mL of xylene at 80 1C under an
atmosphere of 1 atm N2 for 24 h. Yield of isolated products.
b
c
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Chem. Commun., 2012, 48, 4698–4700 4699

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well understood yet. We are continuing to study this process in
order to better understand the reaction mechanism and its
potential applications.
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We thank the National Natural Science Foundation of
China (20932002 and 21172076), National Basic Research
Program of China (973 Program) (2011CB808600), Doctoral
Fund of Ministry of Education of China (20090172110014) and
Guangdong Natural Science Foundation (10351064101000000)
for financial support.
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