Unexpected base-promoted synthesis of tetrasubstituted furans via palladium-catalyzed oxidation and cyclization of carbon-carbon triple bond with molecular oxygen

Article abstract of DOI:10.1055/s-0031-1290526

A new approach to the synthesis of tetrasubstituted furans using aromatic alkynes catalyzed by PdClin DMA (N,N-dimethylacetamide)-H with dioxygen as the sole oxidant is described, in which the oxygen atom of the furan was from water. The preliminary mechanistic understanding of this transformation was investigated. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290526

1074▌
LETTER
lUettner expected Base-Promoted Synthesis of Tetrasubstituted Furans via
Palladium-Catalyzed Oxidation and Cyclization of Carbon–Carbon Triple
Bond with Molecular Oxygen
A Facile Synthesis of Tetrasubstituted Furans
Lianyue Wang,a–c Jun Li,a,c Ying Lv,a,c Gongda Zhao,a,c Shuang Gao*a,c
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, P. R. of China
b
Graduate School of the Chinese Academy of Sciences, Beijing 100049, P. R. of China
c
Dalian National Laboratory for Clean Energy, DNL, 457 Zhongshan Road, Dalian, Liaoning 116023, P. R. of China
Fax +86(411)84379248; E-Mail: junli@dicp.ac.cn; E-Mail: sgao@dicp.ac.cn
Received: 05.01.2012; Accepted after revision: 14.02.2012
Initially, we wanted to investigate the Wacker-type oxida-
Abstract: A new approach to the synthesis of tetrasubstituted fu-
tion of alkynes into 1,2-diketones. The investigation was
rans using aromatic alkynes catalyzed by PdCl2 in DMA (N,N-di-
first carried out with 1,2-diphenylethyne as a model sub-
methylacetamide)–H2O with dioxygen as the sole oxidant is
described, in which the oxygen atom of the furan was from water.
strate in DMA–H2O in the presence of a catalytic amount
The preliminary mechanistic understanding of this transformation of PdCl2 and NaOAc.8 The desired product 1,2-diketones
was investigated.
was obtained in 2% yield and the major product was 2a in
82% yield from GC–MS analysis. The product 2a was fur-
ther isolated and confirmed as tetrasubstituted furan by
NMR (Scheme 1). The unexpected results encouraged us
to further investigate the reaction. The transformation of
1,2-diphenylethyne was tested in the presence of H218O.
The 18O-labled product 2a was detected. The result re-
vealed that the oxygen atom of the 2a was from water in-
stead of molecular oxygen (Scheme 1).
Key words: palladium, oxidation, furans, alkynes, molecular oxy-
gen
Polysubstituted furans are important intermediates in syn-
thetic chemistry as are five-membered heterocyclic struc-
tural components in many natural products and
pharmaceuticals.1 Therefore, a tremendous number of ap-
proaches for their synthesis have been developed.2 Typi-
cally, the methodologies to prepare substituted furans
involve the functionalization of existing furan precursors
or construction of the heterocyclic core by cyclization of
acyclic substrates.3 The former methods occur mainly via
electrophilic substitution reaction. But these methods are
mostly limited to the stability of furans under acidic and
aerobic conditions.1c–e The vast majority of the approach-
es to furan synthesis are based on the latter methods.
Among these protocols, alternative strategies have ex-
plored transition-metal-catalyzed cycloisomerization of
allenyl ketones, alkynyl ketones,4 alkynyl alcohols,5 or
epoxides.6 However, these procedures need to prepare
rather advanced starting materials. Therefore, the devel-
opment of new synthetic routes using readily accessible
starting materials should be paid great attention. Very re-
cently, Jiang reported palladium-catalyzed oxidation and
Lewis acid catalyzed cyclization of alkynes to synthesize
tetrasubstituted furans.7 Lewis acid was necessary to com-
plete this process, but the reaction did not proceed under
air atmosphere in Jiang’s catalytic system. In this paper,
we describe a novel base-promoted oxidation and cycliza-
tion of alkynes catalyzed by PdCl2 in DMA–H2O with
molecular oxygen or air as the sole oxidant, in which H2O
was the reactant. The alkynes substrates were easily pre-
pared by Sonogashira reaction.
Based on the transformation of particular interest, we
started to optimize reaction conditions including palladi-
um sources, solvents and bases. Palladium sources were
first screened to examine their catalytic activities on the
synthesis of tetrasubstituted furan using the model sub-
strate 1,2-diphenylethyne. It was found that without palla-
dium the reaction did not occur (Table 1, entry 1). When
Pd(OAc)2 was used as the catalyst, only a trace amount of
the desired product was obtained (Table 1, entry 2).
Pd2(dba)3 had no catalytic activity for this transformation
(Table 1, entry 3). PdCl2 gave the highest yield (82%) of
2a (Table 1, entry 4). Screening of various solvents
showed that DMA–H2O gave the best result (Table 1, en-
tries 5–7). When the reaction was performed in clean wa-
ter, poor yield was obtained (Table 1, entry 8). This might
be due to the poor solubility of the 1,2-diphenylethyne.
Subsequently, various bases were screened using PdCl2 as
the catalyst in DMA–H2O. Only 19% yield of 2a was ob-
tained when no base was added, indicating that the base is
essential for this catalytic transformation (Table 1, entry
9). It was found that acetates were effective (Table 1, en-
tries 10 and 11). Li2CO3 could also give good result (Table
1, entry 12). Other bases such as K2CO3and Na2CO3 were
less effective (Table 1, entries 13 and 14). Another impor-
tant advantage of this catalytic system is that good yield
could also be obtained when using air instead of pure di-
oxygen (Table 1, entries 15 and 16).
SYNLETT 204012, 237, 1074–1078
Advanced online publication: 29.03.2012
DOI: 10.1055/s-0031-1290526; Art ID: ST-2012-W0008-L
© Georg Thieme Verlag Stuttgart · New York
Using the optimized reaction conditions, we turned our at-
tention to the examination of scope and limitation of this
catalytic oxidation system. As shown in Table 2, both
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
A Facile Synthesis of Tetrasubstituted Furans
1075
O
O
PdCl2, NaOAc
+
DMA–H2O, O2, 80 °C
O
1a
2%
2a
82%
18O
PdCl2, NaOAc
DMA–H218O, O2, 80 °C
1a
2a
Scheme 1
Table 1 Optimization of Reaction Conditions for the Synthesis of
Table 2 Oxidation and Cyclization of Alkynes Catalyzed by the
Tetrasubstituted Furansa
PdCl2/NaOAc Systema
Ar
O
Yield (%)b
Entry
Catalyst
Base
Solvent (v/v)
Ar
Ar
Ar
PdCl2, NaOAc
Ar
+
DMA–H2O, O2, 80 °C
1
2
3
4
5
6
7
–
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
–
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
dioxane–H2O
DMF–H2O
MeCN–H2O
H2O
N.R.
trace
N.R.
82 (76)
33
Ar
Ar
Ar
Pd(OAc)2
Pd2(dba)3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Yield (%)b
Entry
Ar
Product
1
2
2a
2b
76
1a
1b
54
78
71
20
8c
9
12
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
DMA–H2O
19
3
4
2c
10
11
12
13
14
LiOAc
KOAc
Li2CO3
K2CO3
Na2CO3
NaOAc
NaOAc
75
1c
79
69
2d
60
33
1d
2
MeO
5
6
7
2e
2f
43
55
41
15d
16e
48
1e
85 (77)
F
a Reaction conditions: 1,2-Diphenylethyne (0.5 mmol), catalyst (5
mol%), base (5 mol%), solvent (2:0.1), 80 °C, 1 atm O2, 6 h.
1f
b Determined by GC; number in parentheses shows isolated yield.
c H2O: 2 mL.
Br
2g
d Under 1 atm air in 6 h.
e Under 1 atm air in 12 h.
1g
a Reaction conditions: 1,2-Diphenylethyne (0.5 mmol), PdCl2 (5
mol%), NaOAc (5 mol%), DMA–H2O (2:0.1), 80 °C, 1 atm O2.
b Isolated yield.
electron-rich and electron-deficient symmetrical alkynes
could be transformed into the desired products in good
yields. Substrate with a p-OMe substituent led to lower
yield than with a p-Me or m-Me. It is well known that pal-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1074–1078

1076
L. Wang et al.
LETTER
ladium-catalyzed cross-coupling reaction of aryl C–Br cess (Scheme 3). (4) The stoichiometric reaction under a
bond is prone to occur. In the present transformation pro- nitrogen atmosphere revealed that Pd(II) was active cata-
cess aryl bromide could be tolerated and provided 2g in lyst (Scheme 3). (5) A highly informative experiment,
41% yield.
performed with H218O, revealed that the oxygen atom of
the furan was from water instead of molecular oxygen
(Scheme 1). In addition, it was reported that DMA could
promote the reoxidation of the Pd(0) species by O2.9 We
reckoned that the role of molecular oxygen was only to
oxidize Pd(0) to active Pd(II) species in the present cata-
lytic system.
Although we do not know the exact process of this trans-
formation, much effort has been expended on understand-
ing the mechanism. Various experiments were performed
to explore the reaction process. The results are summa-
rized in the following sections: (1) Several compounds
were detected from GC–MS. We proposed one of them as
the key intermediate. These species were allowed to react On the basis of our work and the pertinent literature,
under the optimal reaction conditions. The results re- Scheme 4 shows a plausible reaction mechanism for the
vealed that none of them gave the desired product 2a Pd-catalyzed oxidation and cyclization process. Vinylpal-
(Scheme 2). It should be noted that 1,4-dione 3 was as an ladium species B is formed via formation of Pd(II)–π
intermediate for the formation of the furans in Jiang’s sys- complex A followed by nucleophilic addition by H2O in
tem.7 (2) The transformation of 1a to 2a in the presence of the presence of base. Subsequently, another molecular a
a radical inhibitor such as 2,6-di-tert-butylphenol could addition of the vinylpalladium species B affords species
afford the desired product 2a in 70% yield, suggesting that C. The elimination of HPdCl from C yields the desired
the main reaction pathway might not be a free radical pro- product D, and HPdCl decomposes to Pd(0). The Pd(0)
cess (Scheme 3). (3) Other oxidants such as BQ could pro- species is oxidized to Pd(II), thus completing the catalytic
vide the desired product 2a in 17% yield, revealing the cycle.
existence of Pd(0) to Pd(II) oxidation in the reaction pro-
O
O
O
PdCl2 (5 mol%),
NaOAc (5 mol%)
DMA–H2O,
O2 (1 atm), 80 °C
3
2a
no reaction
O
O
PdCl2 (5 mol%),
NaOAc (5 mol%)
DMA–H2O,
2 (1 atm), 80 °C
O
4
O
2a
no reaction
O
O
O
PdCl2 (5 mol%),
NaOAc (5 mol%)
DMA–H2O,
O
2 (1 atm), 80 °C
5
2a
no reaction
O
PdCl2 (5 mol%),
NaOAc (5 mol%)
O
DMA–H2O,
O2 (1 atm), 80 °C
6
2a
no reaction
Scheme 2 Preliminary mechanistic exploration
Synlett 2012, 23, 1074–1078
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Facile Synthesis of Tetrasubstituted Furans
1077
PdCl2 (5 mol%), NaOAc (5 mol%)
O
DMA–H2O, O2 (1 atm), 80 °C
BHT (120 mol%)
1a
2a
70% yield
PdCl2 (5 mol%), NaOAc (5 mol%)
O
benzoquinone (120 mol%), 80 °C
DMA–H2O, under N2
1a
2a
17% yield
PdCl2 (0.1mmol), NaOAc (0.1 mmol)
DMA–H2O, 80 °C, under N2
O
1a
2a
65% yield
Scheme 3 Control experiments
the reaction and further understand the reaction mecha-
nism of this transformation are in progress.
H2O
Ar
Ar
PdII
a
O2
Acknowledgment
Pd0
Ar
Ar
We gratefully acknowledge financial support from the National Na-
tural Science Foundation of China (No 20643006), the Scientific
Research Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry and the National Basic Research Program
of China (2009CB623505).
A
PdII
base
H2O
Cl
Ar
OH
Ar
Pd
H
ClPdII
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
B
Ar
Ar
Ar
insertion
O
Ar
Ar
References and Notes
HO
Ar
Ar
Ar
ClPd
Ar
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1074–1078

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L. Wang et al.
LETTER
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Synlett 2012, 23, 1074–1078
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