Nano-Cu2O-catalyzed formation of C-C and C-O bonds: One-pot domino process for regioselective synthesis of α-carbonyl furans from electron-deficient alkynes and 2-Yn-1-ols

Article abstract of DOI:10.1002/chem.201000807

The formation of carboncarbon and carbon-oxygen bonds continues to be an active and challenging field of chemical research. Nanoparticle catalysis has attracted considerable attention owing to its environmentally benign and high activity toward the reactions. Herein, we described a novel and effective nano-Cu₂O-catalyzed one-pot domino process for the regioselective synthesis of α-carbonyl furans. Various electron-deficient alkynes with 2-yn-1-ols underwent this process smoothly in moderate to good yields in the presence of air at atmospheric pressure. It is especially noteworthy that a novel 2,4,5-trisubstituted 3-ynylfuran was formed in an extremely direct manner without tedious stepwise synthesis. Additionally, as all of the starting materials are readily available, this method may allow the synthesis of more complex α-carbonyl furans. An experiment to elucidate the mechanism suggested that the process involved a carbene intermediate.

Full text of DOI:10.1002/chem.201000807

FULL PAPER
DOI: 10.1002/chem.201000807
À
À
Nano-Cu2O-Catalyzed Formation of C C and C O Bonds:
One-Pot Domino Process for Regioselective Synthesis of a-Carbonyl Furans
from Electron-Deficient Alkynes and 2-Yn-1-ols
Hua Cao, Huanfeng Jiang,* Gaoqing Yuan, Zhengwang Chen, Chaorong Qi, and
Huawen Huang[a]
Abstract: The formation of carbon–
carbon and carbon–oxygen bonds con-
tinues to be an active and challenging
field of chemical research. Nanoparti-
cle catalysis has attracted considerable
attention owing to its environmentally
benign and high activity toward the re-
actions. Herein, we described a novel
and effective nano-Cu2O-catalyzed
one-pot domino process for the regio-
selective synthesis of a-carbonyl furans.
Various electron-deficient alkynes with
2-yn-1-ols underwent this process
smoothly in moderate to good yields in
the presence of air at atmospheric pres-
sure. It is especially noteworthy that a
novel 2,4,5-trisubstituted 3-ynylfuran
was formed in an extremely direct
manner without tedious stepwise syn-
thesis. Additionally, as all of the start-
ing materials are readily available, this
method may allow the synthesis of
more complex a-carbonyl furans. An
experiment to elucidate the mechanism
suggested that the process involved a
carbene intermediate.
Keywords: copper
·
domino
reactions · furans · nanoparticles ·
regioselective synthesis
Introduction
formation of carbon–carbon and carbon–oxygen bonds is a
major objective.[2]
Transition-metal-catalyzed domino reactions are versatile
tools for the preparation of complex and diverse heterocy-
clic compounds from readily accessible starting materials in
a single operation under mild conditions.[1] The protocol to
achieve this goal is a critical part of much organic synthesis
and remains a continuing challenge that reflects the growing
needs for the pharmaceutical, food, and agricultural indus-
tries. In the past few years, organic chemists have been ex-
pected not only to design new chemical reactions for the for-
mation of carbon–carbon and carbon–oxygen bonds but also
to improve the catalyst systems to maximize resource uti-
lization and to decrease waste, especially for environmental
health and safety. Hence, the search for an inexpensive, en-
vironmentally friendly, and nontoxic catalyst system for the
In this context, nanoparticle catalysts have been widely in-
vestigated[3] and have shown good catalytic activities due to
their high surface areas and reactive morphologies.[4] In
comparison with homogeneous catalysts, heterogeneous cat-
alysts have advantages with respect to product and catalyst
isolation, catalyst reuse, operational handling, and environ-
mental considerations.[5] Also, there has been increasing em-
phasis on the use and development of environmentally
friendly solid-catalyst systems to reduce the amount of toxic
waste.[6] Therefore, more and more organic-synthesis chem-
ists have focused much of their attention on the application
of nanoscience and technology, such as organic transforma-
tions and nanocatalysts.[7]
Furans are important fine chemicals that exhibit a wide
range of biological activities,[8] and many naturally occurring
compounds[9] contain the furan skeleton as a key structural
unit, such as pseudopterolide A[10] and kallolide A[11]. It
should be noted that a-carbonyl furans have been extensive-
ly used as building blocks for the synthesis of more elabo-
rate heterocyclic compounds (Scheme 1).[12] Although sever-
al transition-metal-catalyzed reactions have been reported
for the synthesis of furan derivatives during the last few
years,[13] there has only been a rare example for the synthe-
[a] H. Cao, Prof. H. Jiang, Prof. G. Yuan, Z. Chen, C. Qi, H. Huang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. of China)
Fax : (+86)20-87112906
E-mail: jianghf@scut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000807.
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tigate their activity, and we found that Cu2O nanoparticles
can be utilized as an effective heterocatalyst to accomplish
the reaction through the formation of carbon–carbon and
carbon–oxygen bonds. Herein, we report the successful ex-
tension of the scope of this new catalytic system to various
electron-deficient alkynes with 2-yn-1-ols by using air oxida-
tion under atmospheric pressure and we disclose a novel
and effective method for the synthesis of a-carbonyl furans.
Results and Discussion
Based on our previous work, we focused on searching for
different catalysts and suitable reaction conditions (Table 1)
by using 1a and 2a as the starting materials. In a typical pro-
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. a) General method for the synthesis of the natural product
(À)-epi-swainsonine from furan-2-carbaldehyde. b) Synthesis of useful in-
termediate pyranones from furan-2-carbaldehydes. BH3–DMS: borane–
dimethylsulfide; DMAP: 4-dimethylaminopyridine; NBS: N-bromosucci-
nimide; RT: room temperature; TBABr: tetrabutylammonium bromide;
TBS: tert-butyldimethylsilyl; THF: tetrahydrofuran; TsCl: toluene-4-sul-
fonyl chloride.
Entry Catalyst
Air/O2 (pressure
[atm])
T
Yield
[%][b]
[oC]
1
5 mol% CuI
air
air
air
80
80
120
80
80
80
80
80
80
80
80
80
80
–
2
3
5 mol% Cu2O
5 mol% Cu2O
<5
<5
–
–
–
4
5 mol% Ru3(CO)12 air
5
5 mol% PdCl2
air
air
air
air
6
7
5 mol% Pd
5 mol% Pd
G
R
–
sis of a-carbonyl furans.[14] Therefore, the design and devel-
opment of a new method to synthesize a-carbonyl furans is
essential.
Very recently, we reported a novel one-pot CuI-catalyzed
domino process for the regiospecific synthesis of highly
functionalized polysubstituted furans (Scheme 2).[15] Un-
8
5 mol% NiSO4
trace
62
67
46
41
58
9
5 mol% nano-Cu2O air
10
11
12
13
5 mol% nano-Cu2O O2 (1)
5 mol% nano-Cu2O O2 (3)
5 mol% nano-Cu2O O2 (5)
10 mol% nano-
Cu2O
O2 (5)
O2 (1)
air
14
15
16
17
18
10 mol% nano-
Cu2O
10 mol% nano-
Cu2O
10 mol% nano-
Cu2O
10 mol% nano-
Cu2O
80
69
68
65
75
–
80
air
100
50
air
Scheme 2. CuI-catalyzed synthesis of an a-carbonyl furan. DABCO: 1,4-
diazabicyclo
N
10 mol% nano-
Cu2O
air
RT
[a] dba: trans,trans-dibenzylideneacetone. [b] Yields determined by GC
analysis.
fortunately, this domino process cannot take place when
ethyl phenylpropionate was employed as the substrate to re-
place diethyl but-2-ynedioate (Scheme 3). In addition, it is
needful to probe the proposed mechanism. To solve these
problems, we first broadened the range of catalysts to inves-
cedure, 1a (0.5 mmol), 2a (0.5 mmol), and PBu3 were stirred
in CH2Cl2 at room temperature.[16] The solution was then
evaporated to dryness under reduced pressure. Subsequent-
ly, a variety of catalysts were examined. As shown in
Table 1, the desired product 3aa could not be formed by
using CuI as the catalyst (Table 1, entry 1). It was found that
the desired product was detected when CuI was substituted
by Cu2O (Table 1, entry 2). We then assumed that an in-
crease of temperature may influence the production of 3aa.
However, it was observed that the yield of 3aa did not
Scheme 3. Synthesis of the furan from 1a and 2a cannot be completed.
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Regioselective Synthesis of a-Carbonyl Furans
FULL PAPER
change significantly, even at 1208C (Table 1, entry 3). Other
late-transition-metal catalysts, such as Ru3(CO)12, PdCl2, Pd-
ACHTUNGTRENNUNG(OAc)2, PdACHTUNGTRENNUNG(dba)2, and NiSO4 (Table 1, entries 4–8), were
employed; no conversion was observed in these cases.
Stimulated by the result that Cu2O could catalyze the reac-
tion, we attempted to prepare Cu2O nanoparticles. Accord-
ing to previous reports,[17] Cu2O microcrystals were synthe-
sized by a simple hydrothermal method. The formation of
the nano-Cu2O particles was confirmed by XRD (Figure 1a)
and SEM analysis (Figure 2).
12). It was found that the yield increased to 67% when O2
at 1 atm was used (Table 1, entry 10). However, when higher
pressure O2 was used (Table 1, entries 11 and 12), the yield
decreased gradually, which indicated that the nano-Cu2O
particles were oxidized to CuO at high oxygen pressure. In-
spired by the above results, we attempted to change the
amount of catalyst to improve the yield of 3aa. The results
showed that moderate yields were obtained by using
10 mol% of nano-Cu2O particles (Table 1, entries 13–16).
Interestingly, a good yield was achieved by using 10 mol%
of nano-Cu2O particles under 1 atm of air at 508C (Table 1,
entry 17). Subsequently, we turned our attention to catalyst
reuse. It is noteworthy that 65% yield was maintained even
when the catalyst was reused twice.
Next, under the optimized reaction conditions (Table 1,
entry 17), the reactions of a number of electron-deficient al-
kynes with 2-yn-1-ols were examined (Table 2). We discov-
ered that the reactions between ethyl phenylpropionate (1a)
and differently substituted 2-yn-1-ols (R3 is H, CH3, phenyl,
m-tolyl, 4-methoxyphenyl, 4-nitrophenyl, 2-pyridyl, 2-thio-
phenyl) were successful, and the corresponding products
(3aa–3ah) were obtained in good yields in most cases
(Table 2, entries 1–8). These results indicated that this
domino reaction tolerates functional groups at different po-
sitions of the aromatic ring. There was no effect on this
transformation from either electron-rich or electron-with-
drawing groups on the aromatic ring. Notably, no other re-
gioisomers were detected, which indicated that this cycliza-
tion was regioselective and chemoselective. To further
expand the scope of this methodology, other electron-defi-
cient alkynes, 1b–1d, were surveyed. The results showed
that ethyl but-2-ynoate and aryl alkynyl ketones were also
tolerated under the reaction conditions and afforded the
corresponding products in good yields (Table 2). The molec-
ular structure of representative product 3cc was determined
by X-ray crystallography (Figure 3).
Figure 1. a) XRD pattern of Cu2O particles. b) XRD pattern of nano-
Cu2O particles after undergoing the reaction twice.
As an extension of the above study, we continued to in-
vestigate the scope of this transformation by using diethyl
Figure 2. SEM image of the nano-Cu2O particles.
Surprisingly, the yield of 3aa dramatically increased to
62% (Table 1, entry 9) when nano-Cu2O particles (5 mol%)
were tested in DMF under atmospheric pressure. We then
tried to improve the yields by using oxygen instead of air
and by increasing the oxygen pressure (Table 1, entries 10–
Figure 3. X-ray crystal structure of compound 3cc.
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H. Jiang et al.
Table 2. Nano-Cu2O-catalyzed synthesis of a-carbonyl furans.
Table 2. (Continued)
Entry Alkyne
2-Yn-1-ol
Product
Yield
[%][a]
Entry Alkyne
2-Yn-1-ol
Product
Yield
[%][a]
11
12
1c
2b
73
70
ethyl 3-phenyl-
propionate (1a) (2a)
prop-2-yn-1-ol
1
2
3
71
67
63
1c
2c
but-2-yn-1-ol
(2b)
1a
1a
1,3-diphenyl-
prop-2-yn-1-one 2a
(1d)
13
14
15
68
73
71
3-phenylprop-
2-yn-1-ol (2c)
3-m-tolyl-
prop-2-yn-1-ol
(2d)
1d
1d
2b
2c
4
5
1a
68
65
3-(4-methoxy-
phenyl)-prop-
2-yn-1-ol (2e)
1a
16
17
18
1d
1d
1d
2e
2 f
2h
71
67
61
3-(4-nitro-
phenyl)-
prop-2-yn-1-ol
(2 f)
6
7
1a
66
69
3-(pyridin-2-
yl)-prop-2-yn-
1-ol (2g)
1a
1a
3-(thiophen-2-
yl)-prop-2-yn-
1-ol (2h)
8
62
60
67
[a] Yields of isolated products.
but-2-ynedioate (1e) as a substrate. As indicated in Table 3,
in contrast to 1a–1d, diethyl but-2-ynedioate (1e) gave the
corresponding rearrangement products with good yields
only upon initiation by DABCO. Interestingly, more sterical-
ly hindered ortho-substituted substrates such as 2i or 2j af-
forded the corresponding products in relatively higher yields
when the nano-Cu2O particles were employed as the catalyt-
ic system to substitute CuI in DMF (Table 3, entries 4 and
5).[15] Other substrates can also obtain good yields under the
ethyl but-2-
ynoate (1b)
9
2b
1,3-di-p-tolyl-
10
prop-2-yn-1-one 2a
(1c)
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Regioselective Synthesis of a-Carbonyl Furans
FULL PAPER
Table 3. Nano-Cu2O-catalyzed formation of furans from diethyl but-2-
ynedioate (1e) with different 2-yn-1-ols.
tained under the optimized reaction conditions. This result
demonstrated that regioisomers would be produced because
the two carbonyl groups in complex D (see below) were
both active in the following cyclization reaction.
Finally, the generality of this transformation was also in-
vestigated by using 5-phenylpenta-2,4-diyn-1-ol (2p) and 5-
p-tolylpenta-2,4-diyn-1-ol (2q; Scheme 5). Interestingly, the
desired products 3ap, 3cp, 3eq, and 3hp were formed in 42,
45, 49, and 51% yields, respectively, when 1a, 1c, 1e, and
1h reacted with 2p or 2q. It was especially noteworthy that
these novel 2,4,5-trisubstituted 3-ynylfurans were formed in
an extremely direct manner without tedious stepwise synthe-
sis.
Entry 2-Yn-1-ol
Product Yield
[%][a]
1
2
3
4
5
6
2a
2d
2h
3ea
3ed
3eh
3ei
80
67
72
3-o-tolylprop-2-yn-1-ol (2i)
3-(2-methoxyphenyl)-prop-2-yn-1-ol (2j)
methyl 4-(3-hydroxyprop-1-ynyl)-benzoate 3ek
(2k)
65 (52)[b]
63 (45)[b]
72
3ej
7
8
9
10
3-(2-fluorophenyl)-prop-2-yn-1-ol (2l)
3-(4-ethylphenyl)-prop-2-yn-1-ol (2m)
hept-4-yn-3-ol (2n)
3el
66
73
65
66
Mechanism
3em
3en
3eo
1-phenylhex-1-yn-3-ol (2o)
To gain further insight into the mechanism of this novel con-
version, we envisioned the possibility of trapping the inter-
mediates of the reaction. Recently, Hofmann et al.[18] have
reported the carbene dimer through the reaction of the cop-
per(I) carbene with nucleophilic diazo compounds. Stimulat-
ed by this novel result, we tried to trap copper carbene by
using ethyl 2-diazoacetate (EDA; Scheme 6). 1a (0.5 mmol),
2a (0.5 mmol), and DABCO (0.05 mmol) in CH2Cl2 were
stirred for 15 min at room temperature. The solution was
then evaporated and DMF (3 mL) containing nano-Cu2O
particles (0.3 mmol) was added at 508C. Subsequently, EDA
(0.8 mmol) was added. Interestingly, vinyl furan 5 was ob-
served. However, when 3ea was used as a substrate, com-
pound 5 could not be detected by GC–MS (Scheme 7).
These results indicated that a copper carbene complex was
possibly formed during this domino process.
[a] Yields of isolated products. [b] See reference [15].
To investigate the possible hydrogen migration of the re-
action, an experiment was performed with deuterium-la-
beled prop-2-yn-1-ol at 508C catalyzed by nano-Cu2O parti-
cles (Scheme 8). Compounds 3aD and 4aD were not ob-
served as the products, which indicated that the D atom
can’t migrate to the C4 and C6 positions and is only elimi-
nated by water.
Scheme 4. Synthesis of regioisomeric furans. [a] Isolated yields and the
ratio was determined by H NMR spectroscopy.
1
optimal conditions. It was evi-
dent that the nano-Cu2O parti-
cles were an effective catalyst
for this domino reaction.
The ketone substrates 3-
phenyl-1-(thiophen-2-yl)prop-2-
yn-1-one (1 f) and 3-phenyl-1-p-
tolylprop-2-yn-1-one (1g) were
also examined and this se-
quence
ran
very
well
(Scheme 4). Interestingly, we
found that a pair of isomeric
furans was observed and high
yields of products were ob- Scheme 5. Synthesis of 2,4,5-trisubstituted 2-ynylfurans from 2,4-diyn-1-ols. [a] Isolated yields.
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H. Jiang et al.
underwent cyclization, a [1,3]
hydrogen shift, and oxidation to
form E and E’.[20] The two car-
bonyl groups in complex
D
were both active in the follow-
ing cyclization reaction, so car-
Scheme 6. Formation of compound 5.
bene complexes
E
and E’
would be produced by different
attack directions (paths I and
II) in the presence of a copper catalyst and air. Subsequent-
ly, carbene complexes E and E’ underwent carbene oxida-
tion[21] with oxygen metathesis to give 3 and 4 as the desired
products.
Scheme 7. Unsuccessful reaction of 3ea with EDA.
Conclusion
In summary, we have reported
an unprecedented nano-Cu2O-
catalyzed synthesis of a-carbon-
yl furans through a cyclization/
rearrangement/oxidation
se-
quence of 1,5-enynes. This cata-
lytic system is environmentally
benign and an effective domino
Scheme 8. Deuterium labeling experiment.
À
process for the formation of C
À
On the basis of above experimental results, a plausible re-
action mechanism is shown in Scheme 9. DABCO- or PBu3-
promoted nucleophilic addition of propargyl alcohol to elec-
tron-deficient alkynes formed enyne adduct A. A 6-endo-dig
addition of the enol ether onto the copper(I)–alkyne com-
plex B resulted in the formation of intermediate C, which
collapsed into the b-allenic ketone D.[19] Complex D then
C and C O bonds in modern organic chemistry. It is espe-
cially noteworthy that this domino process is applicable to a
number of electron-deficient alkynes. Furthermore, our find-
ings open a convenient synthetic route to a variety of a-car-
bonyl furans, which are useful synthetic intermediates for
bioactive and natural compounds. The domino reaction ex-
hibits some unusual characteristics that are difficult to un-
derstand at this time and that will be an interesting subject
of mechanistic studies in the future. Hopefully, this research
has established a useful starting point for the investigation
of future applications of the nanoparticle-catalyzed synthesis
of furans.
Experimental Section
General procedure for the synthesis of ethyl 5-formyl-2-phenylfuran-3-
carboxylate: Ethyl phenylpropionate (1a; 0.5 mmol), prop-2-yn-1-ol (2a;
0.5 mmol), and PBu3 (0.05 mmol) were stirred in CH2Cl2 for 30 min at
room temperature. The solution was then evaporated to dryness under
reduced pressure. Subsequently, DMF and nano-Cu2O particles were
added at 508C. After completion of the reaction (monitored by TLC),
water (8 mL) was added. The aqueous solution was extracted with diethyl
ether (3ꢁ8 mL) and the combined extracts were dried with anhydrous
MgSO4. The solvent was removed and the crude product was separated
by column chromatography to give a pure sample of 3aa: IR (KBr): n˜ =
1
2921, 2853, 1683, 1216, 766 cmÀ1; H NMR (CDCl3, 400 MHz): d=9.66 (s,
1H), 8.06–8.08 (m, 2H), 7.64 (s, 1H), 7.45–7.47 (m, 3H), 4.31 (q, J=
7.2 Hz, 2H), 1.33 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d=177.4, 162.2, 161.5, 150.2, 131.0, 129.1, 128.3, 128.2, 123.8, 116.1, 61.2,
14.1 ppm; HRMS (EI): m/z calcd: 244.0736; found: 244.0732.
Scheme 9. Proposed mechanism.
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Regioselective Synthesis of a-Carbonyl Furans
FULL PAPER
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Received: March 31, 2010
Revised: May 14, 2010
Published online: June 30, 2010
Chem. Eur. J. 2010, 16, 10553 – 10559
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10559