Copper-catalyzed C-O bond formation: An efficient one-pot highly regioselective synthesis of furans from (2-furyl)carbene complexes

Article abstract of DOI:10.1021/ol400080e

A convenient one-pot Cu(I)-catalyzed strategy for regioselective synthesis of trisubstituted furan derivatives has been developed via (2-furyl) carbene complexes. This process has opened a new synthetic route to a variety of α-carbonyl furans using air as

Full text of DOI:10.1021/ol400080e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed CÀO Bond Formation:
An Efficient One-Pot Highly Regioselective
Synthesis of Furans from (2-Furyl)Carbene
Complexes
Hua Cao,*,† Haiying Zhan,† Jinghe Cen,† Jingxin Lin,† Yuanguang Lin,† Qiuxia Zhu,†
Minling Fu,† and Huanfeng Jiang*,‡
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University,
Guangzhou 510006, P. R. of China, and School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
caohua@gdpu.edu.cn; jianghf@scut.edu.cn
Received January 12, 2013
ABSTRACT
A convenient one-pot Cu(I)-catalyzed strategy for regioselective synthesis of trisubstituted furan derivatives has been developed via (2-furyl) carbene
complexes. This process has opened a new synthetic route to a variety of R-carbonyl furans using air as the oxidant affording furans in good yields.
Functionalized furans are extremely useful molecules
which exhibit a wide range of biological activities1 and
appear as key structural units in many important pharma-
ceuticals, natural products,2and various materials. Further-
more, furans constitute important scaffolds and blocks
in the construction of complicated organic compounds.
Although many synthetic routes for their preparation have
been developed, this field is still far from being solved. The
development of efficient ways to construct furan mole-
cules from readily available starting materials under mild
conditions continues to attract the interest of organic
chemists due to their remarkable application value.
Transition-metal-catalyzed organic transformations have
become one of the most powerful tools to prepare function-
alized furan molecules in the past few years.3 Among the
transition-metal-catalyzed reactions, Pd,4 Cu,5 Au,6 Ag,7
and Ru8 are the most versatile and widely used metals for the
synthesis of furan derivatives. Despite the efforst of several
research groups to develop elegant transition-metal-catalyzed
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† Guangdong Pharmaceutical University.
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‡ South China University of Technology.
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r
10.1021/ol400080e
XXXX American Chemical Society

processes to form furan derivatives, the synthesis of
R-carbonyl furans via (2-furyl)carbene complexes is still highly
favorable. Fisher carbene complexes are one of the most
versatile organometallic reagents9 and play a critical role in
generating novel molecules in organic transformations.10
Transformation of the carbene complex attracts much atten-
tion, and a number of novel reactions involving this complex
have been reported in modern organic synthesis. Therefore,
in this context, we hope to describe a convenient method
to synthesize R-carbonyl furans via direct oxidation of a
(2-furyl)carbene intermediate by using air as the oxidant.
Recently, we have reported a novel Cu(I)-catalyzed11
domino reaction for the synthesis of R-carbonyl furans via
a rearrangement/dehydrogenation oxidation/carbene oxi-
dation sequence of 1,5-enynes (Scheme 1a). Consequently,
an insightful investigation has been employed to synthesize
R-carbonyl furan derivatives through 5-exodig cyclization
of an ene-yne-ketone,12 which has been demonstrated in
Scheme 1b.
Table 1. Optimization of Reaction Conditionsa
entry catalyst temp (°C) t (h)
solvent
CH2Cl2
yields (%)b
1
CuI
50
50
50
50
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
12
10
8
NPc
NP
NP
NP
NP
10
2
CuBr
CuCl
CuCN
Cu2O
CuI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
CH3CN
DMF
3
4
5
6
7
CuBr
CuCl
CuCN
Cu2O
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
À
75
8
18
9
trace
73
10
11
12
13
14
15
16
17
18
19
20
78
78
4
61
Scheme 1. Synthesis of Furans via (2-Furyl)carbene Complexes
20
8
78
83
8
75
8
77
8
toluene
1,4-dioxane
CH3OH
39
8
73
NPc
8
a Reaction conditions: 3-Phenylpropiolaldehyde (1a 0.5 mmol), pentane-
2,4-dione (2a 0.6 mmol), AcOH (5 mmol %), copper(I) catalyst (3%),
solvent (3 mL), rtÀ50 °C. b GC yields. c No product.
In our initial study, we examined the Cu(I)-catalyzed
one-pot process with various oxidants and solvents to opti-
mize the reaction conditions. 3-Phenylpropiolaldehyde (1a)
and pentane-2,4-dione (2a) were chosen as model substrates,
and the results are described in Table 1. The intermediate
product 3a was easy to prepare. In a typical procedure, 1a
(0.5 mmol), 2a (0.6 mmol), and AcOH (5 mmol %) were
stirred for 30 min in CH2Cl2 (3 mL) at room temperature.
Subsequently, various copper(I) catalysts, such as CuI, CuBr,
CuCl, CuCN, and Cu2O, were tested at 50 °C for 12 h
(Table 1, entries 1À5). However, no product was observed
and the entire intermediate product 3a disappeared by
GCMS, because the reaction may be too severe at 50 °C.
In the next step, the effects of temperature were tested next.
Interestingly, the desired product 4a was obtained in 75%
GC yields, as the reaction was carried out at rt in the presence
of CuBr (Table 1, entry 7). The results showed that this
reaction was highly sensitive to temperature variations. Other
Cu(I)-catalysts, such as CuI, CuCl, CuCN, and Cu2O, were
also effected to generate the corresponding product in mod-
erate to good yields (Table 1, entries 6, 8À10). The reaction
time was also examined, and the results showed that 8 h was
the best choice. Subsequently, we tried to improve the yields
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Org. Lett., Vol. XX, No. XX, XXXX

by examining different solvents. Among the solvents, we were
delighted to find that the product 4a was readily formed in
83% yields in CH3OH (Table 1, entry 15). Other solvents,
such as CH3CN, DMF, toluene, and 1,4-dioxane, were also
afforded in moderate to good yields (Table 1, entries 16À19).
Finally, control experiments revealed that no product was
formed in the absence of CuBr (Table 1, entry 20).
Subsequently, 1b as the substrate was also tested with
various open chain 1,3-dicarbonyl compounds, and the
results indicated that all of the substrates provided similar
isolated yields for the formation of furans. Notably, no
other regioisomers were detected in the reaction, which
indicated that this one-pot transformation was regio- and
chemoselective.
Under the optimized conditions, the substrate scopes were
explored, and the results are described in Scheme 2. First, 1a
was fixed as the substrate to examine a variety of open chain
1,3-dicarbonyl compounds. As shown by the results in
Scheme 2, various open chain 1,3-dicarbonyl compounds
reacted with 1a smoothly. This novel transformation showed
high functional group tolerance (such as R2 = CH3, CH3O,
EtO, (CH3)3CO, p-Cl-PhNH, p-CH3O-PhNH), and in most
cases the corresponding products (4aÀ4f) were obtained in
good yields. When the reaction was carried out using 1,3-
diphenylpropane-1,3-dione as the substrate, only a trace
amount of desired product 4 h was detected by GCMS,
possibly due to the phenyl decreasing nucleophilic nature of
carbonyl during the cyclization process. It is also worth
noting that the reaction was insensitive to the sterically
hindered group (R2 = (CH3)3CO) but sensitive to the
sterically hindered substrate (R3 = (CH3)3C; R2 = CH3O).
For further investigation, commercially available cyclic
1,3-dicarbonyl compounds were employed to explore the
scope of this transformation, and the results are summar-
ized in Scheme 3. Interestingly, it was found that the reaction
would be successfully extended to cyclic 1,3-dicarbonyl
compounds under the optimum conditions and afforded
the corresponding products in good yields, such as 5-methyl-
cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione,
5-phenylcyclohexane-1,3-dione, cyclohexane-1,3-dione, and
5-isopropylcyclohexane-1,3-dione. These results indicated
that the catalytic system is applicable to both open and cyclic
1,3-dicarbonyl compounds.
Scheme 3. CuBr-Catalyzed Synthesis of Furans from 1 with
Cyclic 1,3-Dicarbonyl Compoundsa
Scheme 2. CuBr-Catalyzed Synthesis of Furans via 1a with
Open Chain 1,3-Dicarbonyl Compoundsa
a Isolated yields.
Notably, the 2-vinyl furan derivatives wereformedin the
presence of CuCl2 (5 mol %) in CH2Cl2 at rt, when the
reaction was conducted and carried out using 1b and 2 as
substrates (Scheme 4). This is a novel and efficient trans-
formation to create a CÀC double bond for the construction
of 2-vinylfuran derivatives via Cu-catalyzed 1,2 H-migration.
The new Cu-catalyzed process for the synthesis of trisubsti-
tuted furans was obtained in 41À45% yields.
To our delight, the new furan products were obtained in
moderate yields, when the reaction was carried out in
methanol under anhydrous and anaerobic conditions with
CuBr for 8 h (Scheme 5). Our findings open a novel Cu(I)-
catalyzed synthetic route to prepare methyl ether furans,
initiating further studies and applications on the transfor-
mation which are ongoing in our laboratory.
a Isolated yields.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Cu-Catalyzed Synthesis of 2-Vinyl Furansa
Scheme 7. Proposed Reaction Mechanism
a Isolated yields.
Scheme 5. Cu(I)-Catalyzed Synthesis of Methyl Ether Furansa
1aand 2ahas occurred to generate intermediate 3awhich is
followed by coordination of the Cu(I) species to form
complex A, where Cu(I) is coordinated toa carbonyl group
and the alkyne. And then an intramolecular 5-exodig
cyclization by nucleophilic attack of the carbonyl O-atom
onto C4 has taken place to give the (2-furyl)carbene
complex B which has underwent carbene oxidation with
an oxygen metathesis to generate the desired product 4a.
In conclusion, we have successfully developed a novel
and convenient one-pot Cu(I)-catlyzed approach for the
preparation of 2-carbonyl furans via (2-furyl)carbene
complexes. It provides a versatile synthetic route to form
CÀO bonds via the oxidation of (2-furyl)carbene com-
plexes. Although furan derivatives have been described
from enyne-carbonyl compounds, this method is unique in
that the present process is the first example of the regiose-
lective synthesis of 2-carbonyl furans from an enyne-
carbonyl compound via copper carbene oxidation. More-
over, this unprecedented process is applicable to a variety
of open and cyclic 1,3-dicarbonyl compounds and affords
highly functionalized furans in good yields. Further in-
vestigation into the scope and synthetic applications of
(2-furyl)carbene complexes is being carried out in the future.
a Isolated yield.
Scheme 6. Formation of the Furyl Dimer
To gain further insight intothe mechanism ofthis Cu (I)-
catalyzed transformation, we envision the possibility of
trapping the reaction intermediates. Recently, Barluenga13
reported the Cu(I)-catalyzed process yields the furyl dimer
via a copper(I) carbene complex. Inspired by the result, we
attempted to trap copper carbene (Scheme 6). The reaction
was carried out with CuBr at rt in THF under anhydrous
and anaerobic conditions for 6 h. To our delight, the furyl
dimer (5) was observed by GCMS. The results clearly
indicatedthatthe copper carbene complex possibly formed
during the process.
Acknowledgment. The work was financially supported
by the Foundation for National Natural Science, Foundation
of China (20932002 and 21172076), National Basic Research
Program of China (973 Program) (2011CB808600), Doc-
toral Fund of the Ministry of Education of China (2009-
0172110014), Guangdong Natural Science Foundation
(10351064101000000), and Distinguished Young Talent-
sin Higher Education of Guangdong, China (LYM11083).
Supporting Information Available. Experimental pro-
cedure and characterization of compounds 4aÀ4q, 5aÀ5i,
6aÀ6c, 7aÀ7b. This material is available free of charge via
the Internet at http://pubs.acs.org
On the basis of the above experimental results, a pro-
posed CuBr-catalyzed mechanism has been depicted in
Scheme 7. AcOH-promoted intermoleculardehydrationof
(13) Hofmann, P.; Shishkov, I. V.; Rominger, F. Inorg. Chem. 2008,
47, 11755–11762.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX