Copper(I)-catalyzed synthesis of polysubstituted furans from alkynoates and 1,3-dicarbonyl compounds in the presence of oxygen

Article abstract of DOI:10.1055/s-0029-1219778

A novel and straightforward synthesis of polysubstituted furans was achieved easily from the oxidative cyclization of 1,3-dicarbonyl compound and alkynoate catalyzed by CuI in the presence of O₂.

Full text of DOI:10.1055/s-0029-1219778

LETTER
1071
Copper(I)-Catalyzed Synthesis of Polysubstituted Furans from Alkynoates
and 1,3-Dicarbonyl Compounds in the Presence of Oxygen
S
ynthesis of Poly
u
substituted F
l
urans ong Yan, Jing Huang, Jia Luo, Ping Wen, Guosheng Huang,* Yongmin Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs@lzu.edu.cn; E-mail: liangym@lzu.edu.cn
Received 15 January 2010
yndioate (2a) using air as the oxidant in DMF at 80 °C
(Table 1, entry 1). Fortunately, the expected substituted
furan 3aa was obtained in 72% yield in the presence of
CuI. When O2 was employed as the oxidant, to our de-
light, 85% of 3aa was isolated after 4 hours (entry 2). Oth-
er organic and inorganic oxidants such as PhI(OAc)2,
Abstract: A novel and straightforward synthesis of polysubstituted
furans was achieved easily from the oxidative cyclization of 1,3-di-
carbonyl compound and alkynoate catalyzed by CuI in the presence
of O2.
Key words: polysubstituted furans, oxidant, copper catalysis, oxy-
gen.
Table 1 Optimization of Reaction Conditionsa
O
Polysubstituted furans are one of the important structural
units as well as broadly found in many natural products
and pharmaceutical substances.1 Furthermore many of
polysubstituted furans as important reaction intermediates
have been widely used in the total synthesis and synthetic
industry.2 Due to the importance in organic chemistry, it
has drawn considerable interest for synthetic chemists.
Classical methods for the synthesis of polysubstituted
furans included the cyclocondensation of dicarbonyl
compounds3 and coupling to the exiting furan ring.4 In the
past several years, many efforts for the synthesis of
polysubstituted furans have been made to explore the cy-
cloisomerization of alkyne- and allene-containing cata-
lyzed by transition metals5 such as palladium, copper,
gold, silver, and ruthenium.
CO2Me
MeO2C
Ph
O
O
cat., oxidant
solvent
+
Ph
Ph
MeO2C
Ph
O
CO2Me
3aa
1a
2a
Entry
Catalyst
Oxidant
Solvent
Temp
Yield
(%)b
(°C)
1c
2
CuI
Air
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
72
CuI
80
85
3
CuI
O2
110
r.t.
89
4
CuI
Air
O2
12
5
CuBr
CuCl
CuOTf
Cu(OTf)2
110
110
110
110
110
110
110
110
110
110
110
110
110
76
Recently the C–H activation and cross dehydrogenative
coupling reaction6 for the construction of heterocycles
with simple and readily accessible substrates have re-
ceived great attention and would have a brilliant prospect
for its economic, sustainable, and environmentally friend-
ly features. Oxygen is a very ideal oxidant and offers at-
tractive interest to chemists in term of its tremendous
importance in industry.7 However, using O2 as the oxidant
still remains a challenging research area, and there are
very rare reports about the construction of the polysubsti-
tuted furans via oxidation with O2. So, it will have great
significance to explore the new and efficient strategies for
the synthesis of the furans oxidized by O2. In our ongoing
efforts to explore mild and efficient methodologies for the
synthesis of furans,8 we wish to report a novel and
straightforward method under the mild conditions to syn-
thesize polysubstituted furans in the presence of O2 with
the commercial starting materials.
6
O2
61
7
O2
63
8
O2
47
9
Cu(OAc)2
CuI
O2
45
10d
11d
12
13
14
15
16
17
H2O2
74
CuI
PhI(OAc)2 DMF
n.r.e
7
CuI
O2
O2
O2
O2
O2
O2
THF
CuI
toluene
CHCl3
MeCN
DMF
trace
16
CuI
CuI
13
FeCl2
Pd(OAc)2
n.r.e
n.r.e
DMF
Our preliminary studies focused on the reaction of 1,3-
diphenyl-1,3-propanedione (1a) and dimethyl but-2-
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalysts (10
mol%) in 2 mL of solvent for 4 h.
b Isolated yields.
SYNLETT 2010, No. 7, pp 1071–1074
Advanced online publication: 17.03.2010
DOI: 10.1055/s-0029-1219778; Art ID: W00710ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0
c Reaction time: 2 h.
d Under N2.
e n.r.: no reaction.

1072
R. Yan et al.
LETTER
Cu(OTf)2, Cu(OAc)2, and H2O2 were also evaluated (en-
tries 8–11).
Table 2 Synthesis of Polysubstituted Furans from Alkynoates and
1,3-Dicarbonyl Compoundsa
O
However, O2 was proved to be the most efficient oxidant
in this reaction. Furthermore, different copper salts such
as CuI, CuBr, and CuOTf were examined (entries 5–7)
and other transition metals were also investigated (entries
16 and 17). No better results were obtained. Changing the
solvent to THF, toluene, MeCN, and CHCl3 failed to im-
prove the yields (entries 12–15). The results indicated that
the reaction was sensitive to the solvent medium, and the
use of DMF as a solvent led to high yield. When the reac-
tion was run at room temperature, the product 3aa was ob-
tained in 12% yield even though the reaction was
prolonged to 15 hours (entry 4). Increasing the tempera-
ture to 110 °C, the reaction also proceeded smoothly and
gave the desired furan in 89% yield quickly. The studies
revealed that the preferred temperature for the reaction
was 110 °C, and lower temperature led to long reaction
time and lower yield. Hence, we selected the following
conditions for further experiments: using O2 (1 atm), 1a
(0.5 mmol) and 2a (0.5 mmol) catalyzed by CuI (10
mol%) in DMF (2 mL) at 110 °C.
R3
O
O
R3
R3
R2
R1
CuI (10 mol%), O2 (1 atm)
DMF, 110 °C, 4 h
R1
R2
+
O
R3
2
1
3
1a R1 = R2 = Ph
2a R3 = CO2Me
2b R3 = CO2Et
2c R3 = Ph
1b R1 = Ph, R2 = Me
1c R1 = Ph, R2 = Et
1d R1 = Me, R2 = Me
1e R1 = Me, R2 = OEt
1f R1 = Ph, R2 = OEt
1g R1 = PhNH, R2 = Me
1h R1-R2 = -(CH2)3-
Entry
1
2
3
Yield (%)b
1
2
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ab
3bb
3ac
89
62
3
64
4
45
Under the optimized reaction conditions in hand, we
turned our attention to investigate the scope of the oxida-
tions reactions, and the results are shown in Table 2. 1,3-
Dicarbonyl compounds bearing either phenyl, alkyl, or
heteroatom groups also reacted smoothly and completely
to give polysubstituted furans in fair to good yields. It
seems that the electron density on the 1,3-dicarbonyl com-
pounds drastically affects the reaction and electron-rich
groups play a positive role in the reaction. As an extreme
comparison, the 1,3-diphenyl-1,3-propanedione (1a) af-
forded 89% of the desired product 3aa,11 whereas the di-
methyl but-2-yndioate (2a) was converted to 3da only
in 45% yield (Table 2, entries 1 and 4). In addition, the
different alkynoates were also surveyed in the reaction.
The results showed that the reaction of 1,3-dicarbonyl
compound and dimethyl but-2-yndioate (2a) gave higher
yield than the diethyl but-2-yndioate (2b) and diphenyl-
acetylene (2c). In comparison, the acetylene bearing two
more electron-withdrawing groups will transfer more eas-
ily and lead to higher yield.
5
43
6
47
7
1g
1h
1a
1b
1a
53
8
n.r.c
86
9
10
11
58
trace
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol).
b Isolated yield.
c n.r.: no reaction.
In conclusion, we have developed a facile and direct
method for the construction of polysubstituted furans. Ox-
ygen is firstly used as the oxidant in the synthesis of
polysubstituted furans. The procedure is simple, sustain-
able, and environmentally benign. In addition, the starting
materials are readily available. This reaction proceeds
smoothly in moderate to good yields. Further applications
for the methodology to synthesize natural pharmaceutical
compounds are ongoing in our laboratory, and the results
will be reported in due course.
A plausible mechanism of this reaction is illustrated in
Scheme 1. The reaction may undergo the following steps.
i) the 1,3-dicarbonyl compound is activated with Cu(I) to
give complex 4;9 ii) complex 4 then couples with
alkynoate 3 to produce 5 via Michael addition, and the Cu
catalyst is regenerated, which enters to the next cycle; iii)
a keto–enol equilibrium exists between 5 and 6; iv) com-
pound 6 undergoes a hydride abstraction to form the inter-
mediates 7 and 9 under the oxidation conditions;10 v)
compound 8 is formed from 7 through radical addition; vi)
finally, the furan 3 is generated from the dehydrogenation
process.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the State Key Laboratory of Applied Organic Chemistry
for financial support. We also thank our reviewers’ suggestions.
Synlett 2010, No. 7, 1071–1074 © Thieme Stuttgart · New York

LETTER
Synthesis of Polysubstituted Furans
1073
R3
R3
O
O
R3
R2
R1
R3
R1
O
O
R2
R1
H
7
8
O
O
ICu
OOH–
R2
9
4
Cu2+
R3
O
O
R1
R2
R3
1
2
CuI
O2
H2O2
Cu+
R3
R3
R3
R3
OH
O
O
R3
R1
R1
R2
R1
O
R2
O
R3
R2
O
6
5
3
Scheme 1 Plausible reaction mechanism
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(11) General Procedure for the Preparation of Dimethyl But-
2-yndioate and 1,3-Diphenyl-1,3-propanedione (3aa)
An oven-dried Schlenk tube was charged with CuI (9.5 mg,
0.05 mmol), 1a (0.50 mmol), and 2a (0.50 mmol). The
Schlenk tube was sealed and then evacuated and backfilled
with oxygen (3 cycles). Then DMF (2 mL) was added to the
reaction system. The reaction was stirred at 110 °C under O2
(1 atm) for 4 h. After cooling to r.t., the solvent diluted with
Et2O (10 mL) and washed with brine (5 mL) and dried over
anhyd Na2SO4. After the solvent was evaporated in vacuo,
the residues were purified by column chromatography,
eluting with PE–EtOAc (10:1) to afford pure 3aa.
Dimethyl 4-Benzoyl-5-phenylfuran-2, 3-dicarboxylate
(3aa)
Yellow viscous oil. 1H NMR (400 MHz CDCl3): d = 3.61 (s,
Synlett 2010, No. 7, 1071–1074 © Thieme Stuttgart · New York

1074
R. Yan et al.
LETTER
3 H), 3.96 (s, 3 H), 7.29–7.39 (m, 5 H), 7.50–7.54 (m, 1 H),
7.61–7.63 (m, 2 H), 7.79–7.81 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 52.4, 52.5, 121.5, 126.2, 127.4, 127.6,
128.5, 128.6, 129.3, 130.2, 133.6, 136.7, 141.1, 155.3,
157.7, 161.9, 190.0. IR (neat): 694, 772, 899, 1080, 1167,
1235, 1443, 1666, 1730, 2953, 3004, 3062 cm–1. HRMS
(EI): m/z calcd for C21H16O6 [M + H]+: 365.1020; found:
365.1029.
The 1H NMR, 13C NMR, IR, and HRMS data of 3aa–bb can
be found in the Supporting Information.
Synlett 2010, No. 7, 1071–1074 © Thieme Stuttgart · New York

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