A highly efficient synthesis of 2,5-disubstituted furans from enyne acetates catalyzed by lewis acid and palladium

Article abstract of DOI:10.1055/s-0034-1379213

A highly efficient synthesis of a wide range of 2,5-disubstituted furans from enyne acetates is described. The reactions are conducted by using Lewis acid and palladium catalyst and provide symmetrical and unsymmetrical products in good to excellent yields, with broad substrate scope, including a variety of aromatic and aliphatic substituents in the 2- and 5-position of the furan ring.

Full text of DOI:10.1055/s-0034-1379213

LETTER
▌2341
lAetteHr ighly Efficient Synthesis of 2,5-Disubstituted Furans from Enyne Acetates
Catalyzed by Lewis Acid and Palladium
Synthesis of 2,5-Disubstituted Furans from Enyne Acetates
Zheng-Wang Chen,* Miao-Ting Luo, Yue-Lu Wen, Min Ye, Zhong-Gao Zhou, Liang-Xian Liu*
School of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi, 341000, P. R. of China
Fax +86(797)8393670; E-mail: chenzwang@gnnu.cn
Received: 02.06.2014; Accepted after revision: 11.07.2014
our previous work
this work
Abstract: A highly efficient synthesis of a wide range of 2,5-disub-
stituted furans from enyne acetates is described. The reactions are
conducted by using Lewis acid and palladium catalyst and provide
symmetrical and unsymmetrical products in good to excellent
yields, with broad substrate scope, including a variety of aromatic
and aliphatic substituents in the 2- and 5-position of the furan ring.
Pd(OAc)2
BF3⋅OEt2
I
R1
I2
R1
R2
OAc
R2
MeNO2, H2O
CH2Cl2
O
R1
R2
O
R1 = alkyl, aryl
2 = alkyl, aryl, etc.
R
Key words: furan, enyne acetate, Lewis acid, palladium, synthesis
Scheme 1 Synthesis of substituted furans from enyne acetates by
electrophilic iodocyclization and mediated by Lewis acid and palladi-
um
Furans are one of the most important classes of five-mem-
bered heterocycle compounds, and they are found as key
structural units in many natural products, pharmaceuti-
cals, and agrochemicals.1 Substituted furans are also used
as building blocks in organic synthesis and material sci-
ence.2 The classical approach to furan synthesis is the
Paal–Knorr method, in which 1,4-dicarbonyl compounds
are converted into furan derivatives.3 As an alternative to
classical furan synthesis, several studies have focused on
the development of metal-catalyzed synthesis of furans
employing acyclic precursors. These include the cycliza-
tion of alkynyl,4 allenyl,5 cyclopropenyl,6 and cyclopro-
pyl7 ketone derivatives. Alternative strategies involve the
cyclization of alkynols,8 substituted oxiranes,9 functional-
ized propargyl vinyl ethers,10 enynediones,11 1,3-diynes,12
and other substrates.13
Initial efforts focused on establishing efficient catalysts
and suitable reaction conditions in acetonitrile, with enyne
acetate 1a as the model substrate. As shown in Table 1, the
reaction did not proceed without catalyst (Table 1, entry
1). Several commonly used metal salts were tested as the
catalyst to conduct this reaction and found that whereas
iron and silver salts were inactive for the transformation
(entries 2 and 3), copper and palladium salts could both
smoothly promote the transformation, with palladium ac-
etate being the most efficient (entries 4–10). Previous
work on furan synthesis have shown that Lewis or Brøn-
sted acid favored triple bond activation, thus promoting
subsequent oxygen attack on the triple bond. Different ad-
ditives were therefore tried, and we were pleased to find
that the inclusion of such acids did promote the reaction.
Indeed, furan 2a was obtained in high conversions and
yields when additives were used under the developed con-
ditions (entries 11–14). Compared with Brønsted acid,
Lewis acids were more beneficial to the transformation,
and BF3·OEt2 was found to be the most suitable additive
(entry 14). A control experiment showed that the catalyst
was necessary in the present process (entry 15). We then
screened the effect of solvent on this reaction, and showed
that solvents played an important role in the outcome of
the reaction (entries 17–23). Among the solvents used,
MeNO2 was established as the solvent of choice for the re-
action (entry 22). We considered that the optimized reac-
tion conditions are as follows: 1a (0.25 mmol), H2O (1
equiv), Pd(OAc)2 (5 mol%), BF3·OEt2 (30 mol%), and
MeNO2 at 80 °C for 10 h (entry 22).
2,5-Disubstituted furans are important substructures in
various drugs and drug candidates.14 Although a variety of
well-established methods have proven to be very effective
for the synthesis of 2,5-disubstituted furans,12,15 the search
for efficient routes to substituted furans with flexible sub-
stituent patterns is an important goal of organic synthesis.
Very recently, we reported a convenient and expedient
method for the synthesis of 2,5-disubstituted 3-iodofurans
through electrophilic iodocyclization of enyne acetates.16
As a part of our continuing interest in the construction of
furan derivatives, here we report a synthesis of 2,5-disub-
stituted furans from enyne acetates that is catalyzed by
Lewis acid and palladium and is carried out in the pres-
ence of water (Scheme 1). The approach is convenient for
the construction of both symmetrical and unsymmetrical
2,5-disubstituted furans in good yields with broad func-
tional group compatibilities.
With the optimized conditions in hand, we next focused
on the scope of the reaction (Scheme 2). In general, all of
the substrates tested could form the corresponding 2,5-
disubstituted furans in good to excellent yields. Substitu-
tion at the 2-position of the aromatic ring reduced the
yields slightly (2h, 2j, and 2s). The reaction conditions
SYNLETT 2014, 25, 2341–2344
Advanced online publication: 08.09.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379213; Art ID: st-2014-w0477-l
© Georg Thieme Verlag Stuttgart · New York

2342
Z.-W. Chen et al.
LETTER
Pd(OAc)2 (5 mol%)
BF3⋅OEt2 (30 mol%)
R1
R1
R2
O
OAc
R2
MeNO2, H2O, 80 °C, 10 h
2
1
O
O
O
2a, 91%
2b, 94%
2c, 90%
O
O
O
t-Bu
OMe
2d, 85%
2e, 78%
2f, 86%
F
O
O
O
F
Cl
Cl
2g, 81%
2h, 73%
2i, 86%
F3C
O
O
O
2j, 65%a
2k, 86%
2l, 82%
O
O
O
F
OMe
2m, 91%
2n, 82%
2o, 87%
O
O
O
OMe
F
F
MeO
MeO
F
2p, 80%
2q, 75%
2r, 86%
n-C6H13
O
O
O
F
F
F
F
2s, 73%
2t, 72%
2u, 83%
Scheme 2 Preparation of 2,5-disubstituted furans from enyne acetates (isolated yields). Reagents and conditions: 1 (0.25 mmol), Pd(OAc)2
(5 mol%), BF3·OEt2 (30 mol%), H2O (1 equiv), MeNO2 (1 mL), 80 °C, 10 h. a Reacted for 16 h.
were compatible with alkyl, alkyloxy, aryl, fluoro, chloro, then evaluated the R1 groups on the double bond under the
bromo, and trifluoromethyl groups (2b–u). Initially, a set standard conditions (2m–u). Substrates with either elec-
of substituents at the terminal alkyne moiety were evalu- tron-rich groups (methyl and methoxy) or the electron-de-
ated in the standard conditions (2b–j). Substrates with ei- ficient group (fluoro) attached to the benzene ring could
ther electron-donating or electron-withdrawing groups on produce the 2,5-disubstituted furans in satisfactory yields
the benzene ring could be used to generate the corre- (2m–s). Gratifying, the standard conditions were compat-
sponding products (2b–j). A substrate with the bulky tert- ible with the cyclohexyl group and gave the desired prod-
butyl group afforded the product in 85% yield (2d). The uct in 83% yield (2u).
presence of a CF3 group on the 2-position of benzene ring
led to prolonged reaction time (2j). It should be pointed
A possible mechanism was proposed as outlined in
Scheme 3 on the basis of the reported mechanism17 and
out that carbon–halogen bonds were well tolerated and the
the present results. First, triple-bond coordination to
products containing halogen groups were afforded
Pd(II) occurs to give a π-complex A. The nucleophilic ox-
smoothly. Especially, the aryl chloride could be further
ygen then attacks the Pd-activated triple bond to give 3-
functionalized (2i). Alkynes bearing aliphatic substituents
furylpalladium intermediate B. Finally, B undergoes pro-
were compatible with the reaction system (2k and 2l). We
todepalladation to afford 2,5-disubstituted furans 2. We
Synlett 2014, 25, 2341–2344
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,5-Disubstituted Furans from Enyne Acetates
2343
R1
Table 1 Optimization of Reaction Conditions for the Synthesis of
2,5-Disubstituted Furana
R2
R2
R1
OAc
PdL2
O
2
1
catalyst
additive
O
solvent
OAc
2a
H+
1a
Entry Catalyst
Solvent
Additive
Conv. Yield
R1
Pd(II)
R2
(%)b
(%)c
Pd(II)
OAc
R1
1
2
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
–
–
–
–
R2
O
B
A
FeCl3
–
–
HOAc
H2O
3
AgNO3
–
–
–
Scheme 3 Possible reaction mechanism
4
CuI
–
12
39
55
12
24
40
42
92
98
85
100
55
100
96
95
88
96
96
100
8
5
PdCl2
–
36
51
12
23
35
39
73
68
59
89
–
enyne acetates, which can be prepared from terminal
alkynes.18 The approach is convenient for the construction
of both symmetrical and unsymmetrical products in good
to excellent yield. The results also indicate that the Lewis
acid/palladium catalyzed cyclization reaction tolerates a
wide range of functional groups. Further synthetic appli-
cations and studies of the mechanism of the reaction are
underway in our laboratory.
6
Pd(OAc)2
Pd/C
–
7
–
8
Pd(PPh3)4
PdCl2(PPh3)2
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
–
LiCl
Acknowledgment
ZnCl2
AlCl3
BF3·OEt2
BF3·OEt2
HOAc
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
The authors thank the NSFC (21202023 and 21162001), NSF of
Jiangxi Province (20114BAB213006) and Gannan Normal Univer-
sity for financial support.
Supporting Information for this article is available online
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
40
62
52
79
83
80
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
DMSO
THF
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2341–2344

2344
Z.-W. Chen et al.
LETTER
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(18) Preparation of 2,5-Disubstituted Furans from Enyne
Acetates; Typical Procedure: To a mixture of (Z)-1,4-
diphenylbut-1-en-3-yn-1-yl acetate (1a; 0.25 mmol) and
MeNO2 (1.0 mL), Pd(OAc)2 (5 mol%), BF3·OEt2 (30
mol%), and H2O (1 equiv) were added. The mixture was
stirred at 80 °C for 10 h, then H2O (10 mL) was added and
the solution was extracted with EtOAc (3 × 8 mL). The
combined extract was dried with anhydrous MgSO4, the
solvent was removed, and the residue was separated by
column chromatography (petroleum ether–EtOAc, 30:1) to
give the desired product 2a.
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