Carbon dioxide triggered and copper-catalyzed domino reaction: Efficient construction of highly substituted 3(2H)-furanones from nitriles and propargylic alcohols

Article abstract of DOI:10.1021/ol202241r

A novel carbon dioxide triggered and copper-catalyzed domino reaction for the efficient synthesis of highly substituted 3(2H)-furanones from readily available nitriles and propargylic alcohols has been developed. Carbon dioxide is a prerequisite for achie

Full text of DOI:10.1021/ol202241r

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5520–5523
Carbon Dioxide Triggered and
Copper-Catalyzed Domino Reaction:
Efficient Construction of Highly
Substituted 3(2H)-Furanones from Nitriles
and Propargylic Alcohols
Chaorong Qi, Huanfeng Jiang,* Liangbin Huang, Gaoqing Yuan, and Yanwei Ren
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received August 18, 2011
ABSTRACT
A novel carbon dioxide triggered and copper-catalyzed domino reaction for the efficient synthesis of highly substituted 3(2H)-furanones from
readily available nitriles and propargylic alcohols has been developed. Carbon dioxide is a prerequisite for achieving the present catalytic
transformation, and one of the oxygen atoms of carbon dioxide is incorporated into the 3(2H)-furanones. Nitriles not only act as the reaction
solvent but also as the reactant; copper salts play dual roles of activating both the propargylic alcohols and nitriles.
During the past several decades, the reactions of pro-
pargylic alcohols and carbon dioxide have received much
attention, as they can yieldcyclic carbonates,1 oxazolidinones,2
or carbamates3 under different reaction conditions and use
carbon dioxide as a cheap and safe C1 feedstock. Herein,
we present the first carbon dioxide triggered and copper-
catalyzed domino reaction for the efficient synthesis of
highly substituted 3(2H)-furanones from readily available
nitriles4 and propargylic alcohols (Scheme 1).
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r
10.1021/ol202241r
Published on Web 09/16/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Scheme 1. Reactions Involving Propargylic Alcohols and
Carbon Dioxide
t
conversion of
alcohol (%)
yield (%)b
entry
catalyst
base
DBU
(°C)
3aa (4a/5a)
1
CuI
CuI
CuI
CuI
CuI
rt
>99
>99
>99
>99
0
8 (9/77)
2
DBU
DBU
DBU
DBU
50
70
90
70
70
70
70
70
70
70
70
70
70
70
70
64 (19/À)
82 (À/À)
78 (À/À)
n. r.d
3
4
5c
6
Cu(OTf)2 DBU
CuSO4 DBU
Cu(OAc)2 DBU
>99
>99
>99
>99
>99
>99
>99
73
42 (À/À)
76 (À/À)
48 (À/À)
43 (À/À)
80 (À/À)
36 (trace/À)
61(À/À)
7
8
The 3(2H)-furanones have attracted tremendous inter-
est in biologically active natural product research and
synthetic chemistry.5 A classical approach to substituted
3(2H)-furanones involved acid-catalyzed cyclization/
dehydration of 1-hydroxy-2,4-diketones.5b,c To improve
the synthetic efficiency, many alternative strategies have
been developed, including metal-free processes5d,g,6 as well
astransition-metal-catalyzedcyclizations.7 However, chal-
lenges still remain because (a) most of the current ap-
proaches suffer from limited substrate scope or the lack of
readily available precursors and (b) the synthetic proce-
dures are usually tedious. Therefore, the development of
general routes that allow the facile assembly of substituted
3(2H)-furanonesfrom readily availableandsimplestarting
materials remains an important objective.
9
CuCl2
CuBr2
CuCl
CuBr
CuI
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
10
11
12
13e
14f
15
16
36 (31/À)
65 (23/À)
trace (76/À)
unidentified
mixture
unidentified
mixture
40(À/À)
CuI
>99
>99
>99
AgOAc
PdCl2
17
FeCl2
DBU
70
>99
18
19
20
21
CuI
CuI
CuI
CuI
Et3N
70
70
70
>99
0
DMAP
DABCO
n. r.d
n. r.d
0
Pyridine 70
77
trace (À/59)
a Reaction conditions:1a (0.5mmol),MeCN(2a, 1mL),H2O(1mmol),
catalyst (0.1 mmol), base (0.25 mmol), CO2 (2 MPa), 24 h. b Isolated
yields. c The reaction was carried out under a nitrogen pressure of 2 MPa
in the absence of CO2. d No reaction. e 0.05 mmol of CuI was added.
f 0.125 mmol of DBU was added.
During the course of our continuing investiga-
tions on the reaction between propargylic alcohols and car-
bon dioxide,1g,2c,d,3g,h we observed that 2,2,5-trimethyl-4-
(pyridin-2-yl)furan-3(2H)-one (3aa) formed as a byproduct
together with 3-hydroxy-3-methyl-1-(pyridin-2-yl)butan-2-one
(4a) and (Z)-4,4-dimethyl-5-((pyridin-2-yl)methylene)-1,
3-dioxolan-2-one (5a) when 2-methyl-4-(pyridin-2-yl)but-
3-yn-2-ol (1a) was treated with 20 mol % of CuI in wet
acetonitrile under 2 MPa of CO2 at room temperature
in the presence of 0.5 equiv of 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) (Table 1, entry 1). The formation of
the 3(2H)-furanone 3aa was very unexpected and inter-
esting. It seems that acetonitrile in the reaction acts not
only as a solvent but also as a reactant for the new CÀC/
CÀO bond formation. This surprising finding encour-
aged us to carefully adjust reaction parameters for
the selective generation of 3aa with 1a and acetonitrile
(2a) as well as to elucidate the mechanism of the
transformation.
To our delight, when the reaction temperature was
increased from room temperature to 70 °C, the yield of
the 3(2H)-furanone 3aa was dramatically increased from
8% to 82% although a small amount of unidentified
product was also formed (entry 3), but a further increase
in the temperature above 70 °C resulted in a slight decrease
in the yield of the product (entry 4). It is noteworthy that
when the procedure was performed under a nitrogen
pressure of 2 MPa in the absence of CO2, no reaction
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Org. Lett., Vol. 13, No. 20, 2011
5521

(DABCO) as organic bases the reaction could not proceed
and the starting material was recovered quantitatively
(entries 19 and 20). Pyridine gave 5a as the major product
with a 59% yield (entry 21). Moreover, acetonitrile itself
was found to be the best solvent for the reaction since other
solvents investigated gave poor yields of the product 3aa
(see Supporting Information).
Scheme 2. Scope of Propargylic Alcoholsa,b
The scope of the reaction was then explored with various
propargylic alcohols, and the results are summarized in
Scheme 2. A variety of internal tertiary propargylic alco-
hols with a 2-pyridyl substituent at the acetylenic terminus
were able to undergo the reaction and generated the
corresponding 3(2H)-furanones in moderate to high yields
(3aaÀ3ia). Substrates with an aryl moiety at the acetylenic
position showed less reactivity and usually required a
higher temperature and CO2 pressure. The sterically more
bulky 1l and 1m afforded the desired products in low yields
but with decomposition as a side reaction. The major
byproduct ketones were isolated and determined by GC-
MS. Noteworthy is the functional group compatibility, as
both electron-withdrawing and -donating groups on the
phenyl ring were tolerated. Even 2-quinolinyl and 2-thio-
phenyl substituted propargylic alcohols can undergo this
conversion to generate 3sa and 3ta in relatively lower yields
(38% and 23%, respectively). Unfortunately, propargylic
alcohols with a proton or an alkyl group at the acetylenic
terminus could not undergo the reaction and led predomi-
nantly to decomposition.
Furthermore, various nitriles were employed to probe
the scope of the reaction substrates (Scheme 3). To our
delight, besides acetonitrile, other nitriles such as cyclopro-
panecarbonitrile (2c), benzonitrile (2e), and 2-cyanopyridine
(2f) could undergo the reaction smoothly and gave the
corresponding 3(2H)-furanones in good to high yields.
Valeronitrile (3b) and cinnamonitrile (3d) showed lower
a Reaction conditions: 1 (0.5 mmol), CuI (0.1 mmol), DBU (0.25
mmol), MeCN (1 mL), H2O (1 mmol), CO2 (2 MPa), 70 °C, 24 h.
bIsolated yields. cCO2 (6 MPa), 100 °C.
Scheme 3. Scope of Nitrilesa,b
occurred, indicating that CO2 is a prerequisite for the
transformation (entry 5). Screening of Cu sources showed
that, besides CuI, CuSO4 and CuBr2 are also good cata-
lysts for the reaction (entries 6À12). The loading of the
catalyst CuI and DBU has a significant effect on the
reaction. Reducing the amount of CuI (from 0.2 to
0.1 equiv) or DBU (from 0.5 to 0.25 equiv) resulted in a
decrease in the yield of 3aa together with 4a as the major
byproduct (entries 13 and 14). We also investigated the
catalytic activities of several other metal salts and found
that silver acetate, which has been reported as an efficient
catalyst for the addition of carbon dioxide to propargylic
alcohols to give the corresponding cyclic carbonates,1f
produced 4a in 76% yield under our conditions (entry
15). Palladium(II) chloride and iron(II) chlorideresultedin
the formation of a complex mixture of products (entries 16
and 17). The results in Table 1 also show that the nature of the
organic base has a profound impact on the reaction. Replace-
ment of DBU with triethylamine led to a marked reduction
of the yield of 3aa (entry 18), while with (N,N-dimethyl-
amino)pyridine (DMAP) or 1,4-diazabicyclo[2.2.2]octane
a Reaction conditions: 1a (0.5 mmol), CuI (0.1 mmol), DBU (0.25
mmol), RCN (1 mL), H2O (1 mmol), CO2 (2 MPa), 70 °C, 24 h. bIsolated
yields.
5522
Org. Lett., Vol. 13, No. 20, 2011

water. Subsequent intramolecular Claisen condensation
of 9 provides 10 which eventually affords the product 3 via
dehydration.6h,i
The steps from 5 to 4 and from 4 to 3 were confirmed by
the control experiments (eq 1). Moreover, when the trans-
formation was performed in the presence of H2O18, the
18O-labeled product was not detected (eq 2), indicating
that the oxygen atom of the carbonyl group of the product
3 originated from carbon dioxide.
Figure 1. X-ray structure of 3(2H)-furanone 3oa.
reactivity and produced the corresponding products in low
yields.
A single crystal of product 3oa was obtained by slow
crystallization from a mixture of petroleum ether and ethyl
acetate, and its structure was established by single-crystal
X-ray analysis (Figure 1).
Scheme 4. Plausible Reaction Mechanism
In conclusion, we have demonstrated, for the first time, a
carbon dioxide triggered and Cu-catalyzed domino
process for the synthesis of highly substituted 3(2H)-
furanones from propargylic alcohols and nitriles. This
current approach shows certain advantages due to its
low cost, the readily available catalyst and starting
materials, and its simple experimental procedure.
Work to improve the catalyst efficiency and expand
the substrate range, as well as further experiments to
investigate the mechanism of this reaction, is now in
progress in our laboratory.
Acknowledgment. We thank the National Natural
Science Foundation of China (20932002), the National Basic
Research Program of China (973 Program) (2010CB-
732206), the Doctoral Fund of the Ministry of Education
of China (20090172110014), the Guangdong Natural Science
Foundation (10351064101000000), and the Fundamental
Research Funds for the Central Universities (2011ZZ007)
for financial support.
On the basis of previous reports and our experimental
results, a domino process is proposed in Scheme 4. First,
the reaction is triggered by cycloaddition of CO2 to the
propargylic alcohol 1 in the presence of the copper salt and
DBU, affording the Z-alkylidene cyclic carbonate 5 via 6
and 7.1f,g,2c,d,3g,h Hydrolysis of 5 then occurs to yield the
intermediate 4. Next, copper promotes nucleophilic
attack of 4 on the nitrile 2 to form the intermediate 8,8
which can be converted to the ester 9 in the presence of
Supporting Information Available. Experimental pro-
cedures and characterization of compounds 3aaÀ3af.
This material is available free of charge via the Internet
at http://pubs.acs.org.
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