Base-catalyzed intramolecular 5-exo-dig cyclization of 2-propynyl-1,3- dicarbonyl compounds: An atom-economic route to stereodefined 2-methylene-2,3-dihydrofurans

Article abstract of DOI:10.1002/ejoc.201402542

A new and straightforward base-catalyzed 5-exo-trig cyclization of 2-propynyl-1,3-dicarbonyl compounds leads to the corresponding stereodefined 2-methylene-2,3-dihydrofurans in excellent yields.

Full text of DOI:10.1002/ejoc.201402542

FULL PAPER
DOI: 10.1002/ejoc.201402542
Base-Catalyzed Intramolecular 5-exo-dig Cyclization of 2-Propynyl-1,3-
dicarbonyl Compounds: An Atom-Economic Route to Stereodefined
2-Methylene-2,3-dihydrofurans
Quan Ma,[a] Yeming Wang,[b] Yuegang Zhao,*[a] Peiqiu Liao,[c] Bo Sun,[a] and Xihe Bi*[c,d]
Keywords: Oxygen heterocycles / Spiro compounds / Alkynes / Cyclization / Intramolecular reactions / Base catalysis
A new and straightforward base-catalyzed 5-exo-trig cycliza-
tion of 2-propynyl-1,3-dicarbonyl compounds leads to the
corresponding stereodefined 2-methylene-2,3-dihydrofurans
in excellent yields.
of substituents. 2-Propynyl-1,3-dicarbonyl compounds are
readily available, and the presence of carbonyl and alkynyl
groups in the same molecule skeleton means that they are
useful synthetic intermediates.[5] These compounds have
been widely used for the synthesis of furans by intramolec-
ular oxaannulation (Figure 1a).[6] However, reports regard-
ing the chemoselective formation of 2,3-dihydrofurans are
rarely found in the literature (Figure 1b).[7] Considering the
easy availability of 2-propynyl-1,3-dicarbonyl compounds
and the importance of 2,3-dihydrofurans, it would be very
interesting to prepare 2,3-dihydrofurans starting from 2-
propynyl-1,3-dicarbonyl compounds, especially under
metal-free conditions.
Introduction
2,3-Dihydrofurans, an important class of oxygen hetero-
cycles, are key structural components in many biologically
active natural products and pharmaceuticals,[1] and they are
also useful building blocks in organic synthesis.[2] Because
of their importance, different approaches for the synthesis
of 2,3-dihydrofuran derivatives have been developed. Sub-
stituted 2,3-dihydrofurans have been prepared mainly
by two- or three-component intermolecular cyclization
reactions.[3] Much less attention has been paid to atom-
economic intramolecular heteroannulation reactions, even
though it is also a straightforward and efficient strategy.[4]
To date, only a few intramolecular approaches to the syn-
thesis of 2,3-dihydrofurans are available, and they include:
(1) the nickel-catalyzed rearrangement of 1-acyl-2-vinyl-
cyclopropanes;[4a] (2) the electrophile-induced cyclization/
1,2-migration of 2-alkynyl-2-silyloxy carbonyl com-
pounds;[4b] and (3) the silver-catalyzed cyclization of gem-
difluorohomopropargyl alcohols.[4c] The synthetic methods
developed to date, however, have some drawbacks. For ex-
ample, the starting materials may not be readily available,
and the reactions may require transition-metal catalysts. As
a result of the increased interest in these oxygen hetero-
cycles, there is still demand for new methods that can en-
hance the efficiency of reactions and increase the variety
[a] School of Pharmaceutical Sciences, Changchun University of
Chinese Medicine,
Figure 1. Regioselective intramolecular annulations of 2-propynyl-
1,3-dicarbonyl compounds.
Changchun 130117, China
E-mail: cczyg@126.com
http:/www.bigroup.com.cn/
As part of our ongoing research into the development of
new reactions using functionalized alkynes,[8] we previously
reported a highly efficient iron-catalyzed [4C + 1N] annu-
lation of 2-propynyl-1,3-dicarbonyl compounds with pri-
mary amines, which allowed the synthesis of a variety of
tetrasubstituted and fully substituted pyrroles in good
yields (Figure 1c).[8j] When we subjected 2-propynyl-1,3-di-
carbonyl compounds containing a quaternary carbon cen-
ter at the C-3 position (R2, R3 ϶ H) to the base-catalyzed
[b] Department of Chemistry, Jilin Normal University,
Siping 136000, China
[c] Department of Chemistry, Northeast Normal University,
Changchun 130024, China
E-mail: bixh507@nenu.edu.cn
http://www.bigroup.com.cn/
[d] State Key Laboratory of Elemento-Organic Chemistry, Nankai
University,
Tianjin 300071, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402542.
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Q. Ma, Y. Wang, Y. Zhao, P. Liao, B. Sun, X. Bi
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conditions, cis-2-methylene-2,3-dihydrofurans were formed
Having established the optimal reaction conditions, di-
stereoselectively in high to excellent yields (Figure 1d).[9] verse 2-propynyl-1,3-dicarbonyl compounds (1b–1m) with
The key ring-closing step involves the regioselective 5-exo- varied functional groups (R1–R5) were tested in the cycliza-
dig annulation of the in-situ-generated oxygen anion with tion reaction. As shown in Table 2, all the reactions
the alkyne group. In this paper, we describe this simple and smoothly proceeded to give the corresponding 2-methylene-
atom-economic route to 2,3-dihydrofurans.
2,3-dihydrofurans (i.e., 2b–2m) in good to excellent yields
(76–93%). We found that the reaction time was reduced to
10 min when R1 was changed from an amino group (in 1a)
to an alkyl (Me; in 1b), heteroaryl (2-thienyl; in 1c), or aryl
(Ph; in 1d) group, and the corresponding 2,3-dihydrofurans
(i.e., 2b–2d) were produced in 86, 90, and 80% yields,
respectively (Table 2, Entries 1–3). The electronic properties
of the substituents at the quaternary carbon center affected
the reaction outcome. For example, when the phenyl ring at
R2 was substituted with an electron-donating group, e.g.,
4-MeO (Table 2, Entry 4), the corresponding product was
formed in a slightly higher yield than when it was substi-
tuted with an electron-withdrawing substituent, e.g., 4-Cl
(Table 2, Entry 5). The stereochemistry and the structure of
the 2,3-dihydrofurans were unambiguously confirmed by
the single-crystal X-ray diffraction analysis of product 2f
(Figure 2). As well as electronic effects, steric hindrance has
a great influence on the reaction. When R2 was a bulky 2-
naphthyl group, the reaction time increased to 6 h, and the
corresponding product was formed in 76% yield (Table 2,
Entry 7). In contrast, the substrate in which R2 was 2-thi-
enyl gave the corresponding product (i.e., 2i) in 87% yield
within 50 min (Table 2, Entry 8). Interestingly, the substrate
with an ethyl group as R3 was found to require a much
longer reaction time (240 min) than its phenyl-substituted
counterpart (Table 2, Entries 9 and 10). The electronic
properties of the R4 substituent on the alkyne unit also had
a dramatic influence on the reaction. For example, the reac-
tion of compound 1l, containing a 4-fluorophenyl group,
finished within 15 min, whereas the reaction time for the
Results and Discussion
The reaction conditions were optimized using the reac-
tion of model substrate 1a with different bases and in dif-
ferent solvents, and the results are summarized in Table 1.
With 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base,
most of reactant 1a was recovered when the reaction was
run at 80 °C for 3 h in DMF, DCE (1,2-dichloroethane), or
toluene (Table 1, Entries 1–3), but an excellent yield (92%)
of dihydrofuran product 2a was obtained using pentane-
1,5-diol as the solvent (Table 1, Entry 4). Using ethylene
glycol as the solvent resulted in a slightly lower yield (85%;
Table 1, Entry 5). When the reaction temperature was in-
creased from 80 to 100 °C, we were pleased to find that the
reaction time was shortened to 30 min, and that the product
was formed in 98% yield (Table 1, Entry 6). Other organic
bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and
Et3N were also examined, but no reaction took place
(Table 1, Entries 7 and 8). Inorganic bases were also tested.
With NaOH, the reaction did not go to completion
(Table 1, Entry 9), whereas with Na2CO3 no reaction was
observed (Table 1, Entry 10). Therefore, the conditions
listed in Table 1, Entry 6 [i.e., DBU (1 equiv.), in pentane-
1,5-diol at 100 °C] were found to be optimal, and these con-
ditions were used in subsequent reactions.
Table 1. Optimization of reaction conditions.[a]
Table 2. Scope of the reaction.[a]
Entry
Base
Solvent
T
[°C]
Time
[min]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
DBU[d]
DBU
DBU
DBU
DBU
DMF[e]
DCE[f]
toluene
80
80
80
80
80
180
180
180
180
180
30
30
30
30
30
51 (100)[c]
57 (100)[c]
28 (100)[c]
92
pentane-1,5-diol
ethylene glycol
85
DBU
pentane-1,5-diol 100
pentane-1,5-diol 100
pentane-1,5-diol 100
pentane-1,5-diol 100
pentane-1,5-diol 100
98
DABCO[g]
Et3N
n.r.[h]
n.r.[h]
NaOH
Na2CO3
100 (51)[c]
n.r.[h]
10
[a] Reactions were carried out with 2-propynyl-1,3-dicarbonyl com-
pound 1a (1.0 mmol) and base (1 equiv.) in solvent (2 mL). [b] Iso-
lated yields. [c] The ratio of product 2a to recovered starting mate-
rial 1a (in parentheses) was determined from analysis of the 1H
NMR spectrum of the crude reaction mixture. [d] DBU = 1,8-di-
azabicyclo[5.4.0]undec-7-ene. [e] DMF = N,N-dimethylformamide.
[f] DCE: 1,2-dichloroethane. [g] DABCO = 1,4-diazabicyclo[2.2.2]-
octane. [h] n.r. = no reaction.
[a] Isolated yields.
5000
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Eur. J. Org. Chem. 2014, 4999–5003

A Route to Stereodefined 2-Methylene-2,3-dihydrofurans
substrate 1m, bearing a p-methylphenyl group, was as long propargyl alcohols and 1,3-dicarbonyl compounds, we en-
as 240 min (Table 2, Entries 11 and 12). The formation of visaged that 1n–1q could be suitable substrates for this in-
only the cis isomer of compounds 2 may be ascribed to the tramolecular regio- and stereoselective 5-exo-dig cyclization
steric hindrance and van der Waals repulsion between the reaction, which would lead to spiro-dihydrofurans. To this
R4 and R2/R3.
end, we subjected substrates 1n–1q to the base-catalyzed
procedure (Scheme 1). We were pleased to find that the re-
actions proceeded smoothly in all cases to give the corre-
sponding spiro-dihydrofuran products (i.e., 2n–2q) in excel-
lent yields (81–93%). The regioselectivity in the formation
of product 2p, i.e., reacting at the benzoyl group rather than
the acetyl group, was confirmed by HMBC spectral analy-
sis. It is worth noting that these reactions also produced cis-
configured products stereoselectively.
On the basis of these experimental results and related
precedent,[6,7] a plausible mechanism for this 5-exo-dig cy-
clization reaction is proposed (Scheme 2). First, a proton is
removed from substrate 1 by DBU to give intermediate i.
Subsequently, enol anion ii is generated by keto/enol taut-
omerism. Following regioselective addition of the oxygen
anion to the carbon–carbon triple bond of the alkynyl unit,
an olefinic carbanion intermediate iii is formed. Finally, 2-
methylene-2,3-dihydrofuran 2 is obtained by protonation,
and DBU is regenerated for the next reaction.
Figure 2. X-ray crystal structure of compound 2f.
The spiro-dihydrofuran skeleton has been found in sev-
eral biologically active natural products, including phelligri-
din G, and pleurospiroketals A–E.[10] Therefore, the devel-
opment of efficient synthetic routes to the spiro-di-
hydrofuran skeleton would be very valuable. However,
methods for the synthesis of spiro-dihydrofurans remain
rare. Recently, Shaabani and co-workers reported a facile
three-component reaction between benzo[b]acridine-6,11-
dione, an electron-deficient acetylene compound, and an
isocyanide that led to the formation of spiro-benzo[b]-
acridine-furans.[11] Since cyclic-ketone-derived 2-propynyl-
1,3-dicarbonyl compounds 1n–1q could easily be prepared
through the intermolecular dehydration coupling of tertiary
Scheme 2. Plausible reaction mechanism.
Conclusions
A new and efficient intramolecular regioselective cycliza-
tion of easily available 2-propynyl-1,3-dicarbonyl com-
pounds has been developed. This reaction constitutes a new
and straightforward route to stereodefined 2-methylene-2,3-
dihydrofurans. The advantages of this reaction include an
operationally simple procedure, excellent yields of the prod-
ucts, short reaction times, and a good functional-group tol-
erance. Efforts to extend the scope of this method are ongo-
ing in our laboratory.
Experimental Section
General Remarks: All reagents were purchased from commercial
suppliers, and were used without treatment unless otherwise indi-
cated. Products were purified by column chromatography on silica
gel. 1H and 13C NMR spectra were recorded at 25 °C with a Varian
instrument at 500 and 125 MHz, respectively, and tetramethylsilane
was used as an internal standard. High-resolution mass spectra
Scheme 1. Synthesis of spiro-dihydrofurans.
Eur. J. Org. Chem. 2014, 4999–5003
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Q. Ma, Y. Wang, Y. Zhao, P. Liao, B. Sun, X. Bi
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(HRMS) were recorded with a Bruker microTOF instrument using
the ESI method. CCDC-1011307 (for 2f) contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(500 MHz, CDCl3): δ = 1.84 (s, 3 H), 2.54 (s, 3 H), 4.74 (s, 1 H),
5.08 (s, 1 H), 5.89 (s, 1 H), 7.13–7.16 (m, 1 H), 7.25–7.30 (m, 2 H),
7.32–7.37 (m, 4 H), 7.46 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.1, 26.2, 53.5, 102.5, 114.4, 126.3, 127.9,
128.0, 128.3, 129.3, 133.7, 134.4, 142.4, 163.0, 163.6, 165.9 ppm.
HRMS (ESI-TOF): calcd. for C20H19ClNO2 [M + H]+ 340.1104;
found 340.1108.
Typical Synthetic Procedure (with 2a as an example): Compound
1a (1 mmol, 305.1 mg) and DBU (149.4 μL, 1 mmol) were added
to pentane-1,5-diol (2.0 mL) while stirring. The mixture was
warmed to 100 °C and stirred for 30 min. When TLC showed that
the starting material had been consumed, the reaction mixture was
poured into saturated aqueous sodium chloride (5 mL). The mix-
ture was extracted with dichloromethane (3ϫ 5 mL), and the com-
bined organic extracts were washed with water (3ϫ 5 mL), dried
with MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, petroleum ether/
ethyl acetate, 10:4) to give 2a (299.0 mg, 98%) as a white solid.
(Z)-5-Benzylidene-4-(3-chlorophenyl)-2,4-dimethyl-4,5-dihydro-
1
furan-3-carboxamide (2g): White solid. m.p. 140–142 °C. H NMR
(500 MHz, CDCl3): δ = 1.85 (s, 3 H), 2.56 (s, 3 H), 4.73 (s, 1 H),
5.11 (s, 1 H), 5.73 (s, 1 H), 7.14–7.17 (m, 1 H), 7.25–7.34 (m, 5 H),
7.39–7.40 (m, 1 H), 7.47–7.49 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.1, 26.1, 53.7, 102.6, 114.3, 124.8, 126.3, 126.7,
127.9, 128.3, 130.5, 134.4, 135.1, 146.0, 162.7, 163.9, 165.7 ppm.
HRMS (ESI-TOF): calcd. for C20H19ClNO2 [M + H]+ 340.1104;
found 340.1093.
(Z)-5-Benzylidene-2,4-dimethyl-4-phenyl-4,5-dihydrofuran-3-carbox-
amide (2a): White solid. m.p. 138–140 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.85 (s, 3 H), 2.54 (s, 3 H), 4.76 (s, 1 H), 5.10 (s, 1 H),
5.81 (s, 1 H), 7.11–7.14 (m, 1 H), 7.24–7.30 (m, 3 H), 7.35–7.41 (m,
4 H), 7.46 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 14.0, 26.0, 53.8, 102.1, 114.8, 126.0, 126.6, 127.7, 127.9, 128.2,
129.1, 134.7, 143.7, 163.3, 163.6, 166.2 ppm. HRMS (ESI-TOF):
calcd. for C20H20NO2 [M + H]+ 306.1494; found 306.1487.
(Z)-5-Benzylidene-2,4-dimethyl-4-(naphthalen-2-yl)-4,5-dihydro-
furan-3-carboxamide (2h): Yellow solid. m.p. 221–223 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.97 (s, 3 H), 2.57 (s, 3 H), 4.82 (s, 1 H),
5.10 (s, 1 H), 5.72 (s, 1 H), 7.11–7.14 (m, 1 H), 7.23–7.27 (m, 2 H),
7.36–7.37 (m, 1 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.50–7.56 (m, 2 H),
7.79–7.83 (m, 2 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.1, 26.1, 54.1, 102.5, 114.4,
123.8, 125.8, 126.1, 126.6, 126.7, 127.6, 127.9, 128.0, 128.3, 129.3,
132.5, 133.0, 134.6, 141.1, 163.2, 163.7, 166.1 ppm. HRMS (ESI-
TOF): calcd. for C24H22NO2 [M + H]+ 356.1651; found 356.1640.
(Z)-1-(5-Benzylidene-2,4-dimethyl-4-phenyl-4,5-dihydrofuran-3-yl)-
ethanone (2b): White solid. m.p. 98–100 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.90 (s, 3 H), 1.93 (s, 3 H), 2.55 (s, 3 H), 5.17 (s, 1 H),
7.12–7.15 (m, 1 H), 7.20–7.24 (m, 1 H), 7.26–7.30 (m, 2 H), 7.31–
7.36 (m, 6 H), 7.47–7.49 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.2, 26.5, 29.8, 54.1, 102.4, 123.1, 126.1, 126.3, 126.7,
127.9, 128.2, 128.4, 134.7, 144.8, 163.8, 164.7, 193.9 ppm. HRMS
(ESI-TOF): calcd. for C21H21O2 [M + H]+ 305.1542; found
305.1545.
(Z)-5-Benzylidene-2,4-dimethyl-4-(thiophen-2-yl)-4,5-dihydrofuran-
3-carboxamide (2i): White solid. m.p. 244–146 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.90 (s, 3 H), 2.52 (s, 3 H), 5.15 (s, 1 H),
5.31 (s, 1 H), 5.93 (s, 1 H), 6.97–6.99 (m, 1 H), 7.06–7.09 (m, 1 H),
7.14–7.17 (m, 1 H), 7.27–7.31 (m, 3 H), 7.50 (d, J = 8.0 Hz, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 27.8, 51.7, 102.3,
114.1, 124.5, 126.3, 126.7, 126.9, 128.1, 128.3, 134.5, 149.5, 162.1,
163.6, 166.0 ppm. HRMS (ESI-TOF): calcd. for C18H18NO2S [M
+ H]+ 312.1058; found 312.1044.
(Z)-1-[5-Benzylidene-4-methyl-4-phenyl-2-(thiophen-2-yl)-4,5-di-
1
hydrofuran-3-yl]ethanone (2c): White solid. m.p. 169–171 °C. H
NMR (500 MHz, CDCl3): δ = 2.02 (s, 3 H), 2.17 (s, 3 H), 5.26 (s,
1 H), 7.03–7.04 (m, 1 H), 7.15–7.19 (m, 2 H), 7.23–7.32 (m, 4 H),
7.42–7.44 (m, 3 H), 7.54–7.57 (m, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.5, 26.8, 57.0, 102.1, 122.5, 126.1, 126.5, 126.7,
127.5, 128.0, 128.2, 128.3, 132.5, 133.2, 134.9, 144.3, 145.6, 159.7,
163.8, 183.6 ppm. HRMS (ESI-TOF): calcd. for C24H21O2S [M +
H]+ 373.1262; found 373.1264.
(Z)-5-Benzylidene-2-methyl-4,4-diphenyl-4,5-dihydrofuran-3-carbox-
amide (2j): White solid. m.p. 258–260 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.55 (s, 3 H), 5.03 (s, 1 H), 5.40 (s, 1 H), 5.61 (s, 1 H),
7.15–7.18 (m, 1 H), 7.28–7.32 (m, 4 H), 7.35–7.38 (m, 4 H), 7.44–
7.48 (m, 4 H), 7.51 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.4, 64.3, 106.0, 113.5, 126.5, 127.6, 128.3, 128.4,
128.67, 128.69, 134.5, 142.7, 162.8, 163.7, 166.4 ppm. HRMS (ESI-
TOF): calcd. for C25H22NO2 [M + H]+ 368.1651; found 368.1655.
(Z)-1-(5-Benzylidene-4-methyl-2,4-diphenyl-4,5-dihydrofuran-3-yl)-
ethanone (2d): Yellow liquid. 1H NMR (500 MHz, CDCl3): δ = 1.85
(s, 3 H), 2.03 (s, 3 H), 5.28 (s, 1 H), 7.13–7.15 (m, 1 H), 7.21–7.23
(m, 1 H), 7.25–7.29 (m, 2 H), 7.32–7.35 (m, 2 H), 7.44 (d, J =
8.0 Hz, 2 H), 7.50–7.57 (m, 5 H), 7.71–7.73 (m, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 26.3, 30.2, 56.2, 102.6, 124.4, 126.1,
126.3, 126.7, 128.0, 128.2, 128.3, 128.6, 129.4, 129.9, 131.0, 134.8,
144.8, 162.2, 163.6, 194.2 ppm. HRMS (ESI-TOF): calcd. for
C26H23O2 [M + H]+ 367.1698; found 367.1739.
(Z)-5-Benzylidene-4-ethyl-2-methyl-4-phenyl-4,5-dihydrofuran-3-
carboxamide (2k): White solid. m.p. 175–177 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz, 3 H), 2.08–2.14 (m, 1
H), 2.35–2.43 (m, 1 H), 2.56 (s, 3 H), 4.75 (s, 1 H), 5.08 (s, 1 H),
5.94 (s, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.24–7.29 (m, 3 H), 7.36 (t,
J = 7.5 Hz, 2 H), 7.40–7.43 (m, 2 H), 7.47 (d, J = 7.0 Hz, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 9.0, 13.9, 30.5, 58.7, 102.4
111.5 126.1 126.6, 127.6, 127.9, 128.2, 129.1, 134.8 144.3 161.9,
163.9, 166.2 ppm. HRMS (ESI-TOF): calcd. for C21H22NO2 [M +
H]+ 320.1651; found 320.1654.
(Z)-5-Benzylidene-4-(4-methoxyphenyl)-2,4-dimethyl-4,5-dihydro-
1
furan-3-carboxamide (2e): White solid. m.p. 185–183 °C. H NMR
(500 MHz, CDCl3): δ = 1.82 (s, 3 H), 2.53 (s, 3 H), 3.80 (s, 3 H),
4.84 (s, 1 H), 5.09 (s, 1 H), 5.81 (s, 1 H), 6.89 (d, J = 7.5 Hz, 2 H),
7.12–7.15 (m, 1 H), 7.25–7.30 (m, 2 H), 7.30–7.34 (m, 2 H), 7.47
(d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.0,
26.3, 53.3, 55.2, 101.8, 114.4, 114.7, 126.0, 127.8, 127.9, 128.3,
134.8, 135.6, 158.9, 163.1, 163.9, 166.3 ppm. HRMS (ESI-TOF):
calcd. for C21H22NO3 [M + H]+ 336.1600; found 336.1583.
(Z)-5-(4-Fluorobenzylidene)-2,4-dimethyl-4-phenyl-4,5-dihydro-
furan-3-carboxamide (2l): White solid. m.p. 242–244 °C. H NMR
1
(500 MHz, CDCl3): δ = 1.85 (s, 3 H), 2.55 (s, 3 H), 4.75 (s, 1 H),
5.06 (s, 1 H), 5.53 (s, 1 H), 6.94–6.98 (m, 2 H), 7.29–7.32 (m, 1 H),
7.37–7.45 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.0,
26.1, 53.8, 101.1, 114.8, 115.0 (d, J = 21.0 Hz), 126.6, 127.8, 129.2,
129.4 (d, J = 8.0 Hz), 130.9 (d, J = 3.0 Hz), 143.7, 160.0, 162.0,
(Z)-5-Benzylidene-4-(4-chlorophenyl)-2,4-dimethyl-4,5-dihydro- 163.1, 163.18, 163.20, 163.4, 166.0 ppm. HRMS (ESI-TOF): calcd.
for C20H19FNO2 [M + H]+ 324.1400; found 324.1398.
1
furan-3-carboxamide (2f): Yellow solid. m.p. 206–208 °C. H NMR
5002
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Eur. J. Org. Chem. 2014, 4999–5003

A Route to Stereodefined 2-Methylene-2,3-dihydrofurans
(Z)-2,4-Dimethyl-5-(4-methylbenzylidene)-4-phenyl-4,5-dihydro-
furan-3-carboxamide (2m): White solid. m.p. 240–242 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.84 (s, 3 H), 2.30 (s, 3 H), 2.54 (s, 3 H),
4.75 (s, 1 H), 5.07 (s, 1 H), 5.59 (s, 1 H), 7.08 (d, J = 8.0 Hz, 2 H),
7.28–7.31 (m, 1 H), 7.35–7.40 (m, 4 H), 7.40–7.43 (m, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.1, 21.1, 26.2, 53.7, 102.1,
114.6, 126.6, 127.6, 127.8, 129.0, 129.1, 131.8, 135.8, 143.9, 162.9,
163.5, 166.2 ppm. HRMS (ESI-TOF): calcd. for C21H22NO2 [M +
H]+ 320.1651; found 320.1643.
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(Z)-2-Benzylidene-5-methyl-3Ј,4Ј-dihydro-2H,2ЈH-spiro[furan-3,1Ј-
naphthalene]-4-carboxamide (2n): White solid. m.p. 254–256 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.87–1.89 (m, 1 H), 2.01–2.06 (m, 1
H), 2.14–2.22 (m, 2 H), 2.55 (s, 3 H), 2.80–2.87 (m, 1 H), 2.90–2.97
(m, 1 H), 4.66 (s, 1 H), 5.07 (s, 1 H), 5.32 (s, 1 H), 7.13–7.22 (m, 5
H), 7.26–7.30 (m, 2 H), 7.47–7.50 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.2, 17.3, 29.2, 35.4, 53.9, 104.4, 114.4,
126.2, 127.2, 127.6, 128.1, 128.3, 129.6, 130.1, 134.7, 137.2, 137.5,
163.95, 163.97, 166.0 ppm. HRMS (ESI-TOF): calcd. for
C22H22NO2 [M + H]+ 332.1651; found 332.1645.
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(Z)-2Ј-Benzylidene-5Ј-methyl-2ЈH-spiro[fluorene-9,3Ј-furan]-4Ј-carb-
oxamide (2o): Pale yellow solid. m.p. 275–277 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.68 (s, 3 H), 4.21 (s, 1 H), 4.74, (s, 1 H),
5.24 (s, 1 H), 7.09–7.12 (m, 1 H), 7.21–7.24 (m, 2 H), 7.29–7.35 (m,
2 H), 7.35–7.41 (m, 4 H), 7.41–7.44 (m, 2 H), 7.78 (d, J = 7.5 Hz,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.4, 64.1, 102.3,
110.1, 120.5, 125.0, 126.3, 128.1, 128.2, 128.88, 128.92, 134.3,
139.4, 148.1, 157.6, 165.1, 166.8 ppm. HRMS (ESI-TOF): calcd.
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(Z)-1-(2Ј-Benzylidene-5Ј-phenyl-2ЈH-spiro[fluorene-9,3Ј-furan]-4Ј-
yl)ethanone (2p): White solid. m.p. 221–223 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.56 (s, 3 H), 4.86 (s, 1 H), 7.12–7.13 (m,
1 H), 7.22–7.25 (m, 2 H), 7.32–7.35 (m, 2 H), 7.42–7.44 (m, 6 H),
7.54–7.58 (m, 3 H), 7.81 (d, J = 7.0 Hz, 2 H), 7.95–7.99 (m, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 28.9, 65.6, 102.9, 118.9,
120.4, 124.2, 126.4, 128.2, 128.3, 128.4, 128.5, 129.3, 129.5, 131.3,
134.3, 140.4, 149.1, 157.4, 164.5, 193.5 ppm. HRMS (ESI-TOF):
calcd. for C31H23O2 ([M + H]+) 427.1699; found 427.1695.
(Z)-1-(2Ј-Benzylidene-5Ј-methyl-2ЈH-spiro[fluorene-9,3Ј-furan]-4Ј-
yl)ethanone (2q): White solid. m.p. 212–214 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.20 (s, 3 H), 2.71 (s, 3 H), 4.78 (s, 1 H),
7.10–7.13 (m, 1 H), 7.22–7.25 (m, 2 H), 7.31–7.32 (m, 4 H), 7.39–
7.45 (m, 4 H), 7.79 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.2, 28.1, 64.0, 102.6, 117.7, 120.3, 124.5, 126.4,
128.21, 128.23, 128.5, 134.3, 140.2, 149.0, 157.9, 168.1, 194.8 ppm.
HRMS (ESI-TOF): calcd. for C26H21O2 [M + H]+ 365.1542; found
365.1533.
Supporting Information (see footnote on the first page of this arti-
1
cle): Crystallographic data for compound 2f; copies of H and 13C
NMR spectra; HMBC spectra of 2b and 2q.
Acknowledgments
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see: R. Chenevert, J. Page, R. Plante, D. Beaucage, Synthesis
1982, 75.
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This work was supported by the National Natural Science Founda-
tion of China (NSFC) (21172029, 21202016, 21372038), the Minis-
try of Education of the People’s Republic of China (NCET-13-
0714), and the Jilin Provincial Research Foundation for Basic Re-
search (20140519008JH).
[11] R. Ghadari, F. Hajishaabanha, M. Mahyari, A. Shaabani,
H. R. Khavasi, Tetrahedron Lett. 2012, 53, 4018.
Received: May 7, 2014
Published Online: July 7, 2014
Eur. J. Org. Chem. 2014, 4999–5003
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5003