Experimental and theoretical study of the [3 + 2] cycloaddition of carbonyl ylides with alkynes

Article abstract of DOI:10.1039/c2ob26442k

The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and alkynes (phenylacetylene, methyl propiolate, methyl but-2-ynoate and methyl 3-phenylpropiolate) to give substituted 2,5-dihydrofurans was investigated. The effect of in

Full text of DOI:10.1039/c2ob26442k

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PAPER
Experimental and theoretical study of the [3 + 2] cycloaddition of carbonyl
ylides with alkynes†
Ghenia Bentabed-Ababsa,*a,b Samira Hamza-Reguig,a Aïcha Derdour,a Luis R. Domingo,*c José A. Sáez,c
Thierry Roisnel,d Vincent Dorcet,d Ekhlass Nassare and Florence Mongin*b
Received 24th July 2012, Accepted 11th September 2012
DOI: 10.1039/c2ob26442k
The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and alkynes
(phenylacetylene, methyl propiolate, methyl but-2-ynoate and methyl 3-phenylpropiolate) to give
substituted 2,5-dihydrofurans was investigated. The effect of indium(III) chloride on the outcome of the
reaction was studied in the case of phenylacetylene and methyl propiolate. The thermal reaction between
the carbonyl ylide coming from 2,2-dicyano-3-phenyloxirane and both methyl propiolate and methyl
but-2-ynoate was theoretically investigated using DFT methods in order to explain the reactivity and
regioselectivity observed.
current understanding of the underlying principles in these reac-
Introduction
tions has grown from a fruitful interplay between theory and
experiment.2
Cycloaddition reactions are one of the most important synthetic
processes, with both synthetic and mechanistic interest in
organic chemistry. Among them, [3 + 2] cycloaddition (32CA)
reactions, also named 1,3-dipolar cycloadditions, whose general
concept was introduced by Huisgen and co-workers in 1960s,1
are versatile tools for building five-membered heterocycles, and
Carbonyl ylides, generated by thermal ring opening of epox-
ides, are known to react with π-bonds of alkynes,3 alkenes,3a,b,4
imines,5 aldehydes5c,6 and ketones,7 and thioketones,8 affording
highly substituted dihydrofurans, tetrahydrofurans, oxazolidines,
dioxolanes, and oxathiolanes, respectively. Following recent
studies of the 32CA reactions between, on the one hand, carbo-
nyl ylides and, on the other hand, aldehydes,5c imines,5c and
ketones,7 in which we have performed theoretical calculations
using density functional theory (DFT) methods to depict the
mechanism of these reactions, we here report our studies con-
cerning the reactions involving unsymmetrical alkynes.
Since the first thermal reactions between carbonyl ylides, gen-
erated from epoxides, and activated alkynes (such as methyl
acetylenedicarboxylate) reported more than 40 years ago,3a,b few
studies have been devoted to such an access to dihydrofurans.3c–e
In particular, it was of interest to study, in the light of DFT
calculations, the regioselectivity results obtained by involving
unsymmetrical alkynes in the reaction with carbonyl ylides.
aLaboratoire de Synthèse Organique Appliquée, Faculté des Sciences,
Université d’Oran, BP 1524 El M’Naouer, 31000 Oran, Algeria.
E-mail: badri_sofi@yahoo.fr; Fax: +213-04158-2540;
Tel: +213-79175-8768
bEquipe Chimie et Photonique Moléculaires, Institut des Sciences
Chimiques de Rennes, UMR 6226 CNRS, Université de Rennes 1,
Bâtiment 10A, Case 1003, Campus Scientifique de Beaulieu, 35042
Rennes Cedex, France. E-mail: florence.mongin@univ-rennes1.fr;
Fax: +33-2-2323-6955; Tel: +33-2-2323-6931
cDepartamento de Química Orgánica, Universidad de Valencia,
Dr. Moliner 50, 46100 Burjassot, Valencia, Spain.
E-mail: domingo@utopia.uv.es; Fax: +34-9-6354-4328;
Tel: +34-9-6354-3106
dCentre de Diffractométrie X, Institut des Sciences Chimiques de
Rennes, UMR 6226 CNRS, Université de Rennes 1, Bâtiment 10B,
Campus Scientifique de Beaulieu, 35042 Rennes Cedex, France
eDepartment of Chemistry, Faculty of Women for Arts, Science and
Education, Ain Shams University, Asma Fahmy Street, Heleopolis
(El-Margany), Cairo, Egypt
Results and discussion
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of the compounds 3a–c, 3′b, 5a–c, 5′a–c, 8a–c and 9a–c;
ORTEP diagrams of the compounds 3a–c, 5′a, 5b, 8a and 8b. For the
stationary points involved in the 32CA reactions of CY 1′a with methyl
propiolate (4) and methyl but-2-ynoate (6): B3LYP/6-31G*, B3LYP/6-
311G* and B3LYP/6-311+G* total and relative energies in vacuo and
transition state geometries, B3LYP/6-31G* solvent energies and thermo-
dynamic data, and B3LYP/6-31G* cartesian coordinates. CCDC 3a
(891057), 3b (891058), 3c (891059), 5′a (891060), 5b (891061), 8a
(891062), and 8b (891063). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26442k
Synthetic aspects
We first considered 32CA reactions between 2,2-dicyano-3-
(4-substituted)phenyloxiranes 1a–c9 and terminal alkynes. Using
phenylacetylene (2, 5 equiv.), monitoring the conversion to the
corresponding 2,5-dihydrofurans by TLC showed that the reac-
tions carried out in refluxing toluene were complete after about
40 h. NMR analysis of the crude obtained after removal of the
solvent showed the presence of two regioisomers in each case,
8434 | Org. Biomol. Chem., 2012, 10, 8434–8444
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Table 1 Cycloaddition reaction between carbonyl ylides generated
from the epoxides 1 and phenylacetylene (2)
Table 2 Cycloaddition reaction between carbonyl ylides generated
from the epoxides 1 and methyl propiolate (4)
Product(s),
yield(s) (%)
Product(s),
yield(s) (%)
Entry
X (1)
Catalyst
5 : 5′ ratio
Entry
X (1)
Catalyst
3 : 3′ ratio
1
2
3
4
5
6
H (1a)
—
—
—
24 : 76
26 : 74
29 : 71
33 : 67
31 : 69
18 : 82
5a, 12; 5′a, 40
5b, 10; 5′b, 54
5c, 11; 5′c, 65
5′a, 58
5′b, 57
5c, 8; 5′c, 67
1
2
3
4
5
6
H (1a)
—
—
—
84 : 16
84 : 16
75 : 25
90 : 10
89 : 11
83 : 17
3a, 40
3b, 52; 3′b, 12
3c, 50
3a, 60
3b, 64
Cl (1b)
MeO (1c)
H (1a)
Cl (1b)
MeO (1c)
Cl (1b)
MeO (1c)
H (1a)
Cl (1b)
MeO (1c)
InCl3 (0.1 equiv.)
InCl3 (0.1 equiv.)
InCl3 (0.1 equiv.)
InCl3 (0.1 equiv.)
InCl3 (0.1 equiv.)
InCl3 (0.1 equiv.)
3c, 60
with ratios of 84 : 16, 84 : 16 and 75 : 25 respectively obtained
using 1a (X = H), 1b (X = Cl) and 1c (X = OMe). The major
products 3 were purified by column chromatography over silica
gel, in yields ranging from 40 to 52% whereas 3′b was the only
minor product isolated (12% yield). The observed 1H NMR
coupling constants of 1.8 and 2.1 Hz were respectively attributed
to J4–5 (major regioisomer 3) and J3–5 (minor regioisomer 3′)
on the basis of a previous study.10 The major regioisomers 3
were then identified unequivocally by X-ray structure analysis
(Table 1, entries 1–3†).
Table 3 Cycloaddition reaction between carbonyl ylides generated
from the epoxides 1 and methyl but-2-ynoate and 3-phenylpropiolate
(6,7)
H
H
Entry X (1)
R
Reaction time (h) Product, yield (%)
The same reactions have then been repeated, but in the pres-
ence of indium(III) chloride (0.1 equiv.) which has been recog-
nized as a suitable catalyst for cycloaddition reactions.11
Shortened reaction times of 29 h, 27 h and 20 h increased 3 : 3′
ratios of 90 : 10, 89 : 11 and 83 : 17, and higher yields of 3 (60 to
64%) were respectively noted using 1a (X = H), 1b (X = Cl)
and 1c (X = OMe) under these conditions using 4 equiv. of
phenylacetylene (Table 1, entries 4–6).
1
2
3
4
5
6
H (1a)
Cl (1b)
MeO (1c) Me (6) 24
H (1a)
Cl (1b)
MeO (1c) Ph (7)
Me (6) 48
Me (6) 48
8a, 66
8b, 62
8c, 44
9a, 60
9b, 47
9c, 66
Ph (7)
Ph (7)
96
96
55
We then considered 32CA reactions between 2,2-dicyano-3-
We next turned to the reaction of methyl propiolate (4) with
the 2,2-dicyano-3-(4-substituted)phenyloxiranes 1a,b (4 equiv.)
and 1c (1 equiv.) under the conditions used before. Without a
catalyst, NMR analysis of the crudes showed the formation of
two regioisomers in 24 : 76, 26 : 74 and 29 : 71 ratios, using 1a
(48 h reaction time for complete conversion), 1b (48 h) and 1c
(24 h) respectively. They were separated by column chromato-
graphy over silica gel, and isolated in yields ranging from 10 to
12% and 40 to 65% for the major and minor isomer, respect-
ively. As before,10 the major compounds with the higher 2,5-
dihydrofuran 1H NMR coupling constants (2.1 Hz) were
assigned to the 4-substituted regioisomers 5′ (HJ3–5), and the
minor compounds with the lower 2,5-dihydrofuran 1H NMR
coupling constants (1.5–1.8 Hz) to the 3-substituted regio-
isomers 5 (HJ4–5). This was corroborated by NMR HMQC
sequences performed on 5′c and 5c, and the structures of 5′a
and 5b were confirmed by X-ray diffraction data (Table 2,
entries 1–3†). In the presence of indium(III) chloride (0.1 equiv.),
the reaction times were slightly shortened (36 h in the case of
1a,b and 20 h with 1c), as well as the regioselectivities (Table 2,
entries 4–6).
(4-substituted)phenyloxiranes 1a–c and internal alkynes. Using
methyl but-2-ynoate (6) and methyl 3-phenylpropiolate (7)
without catalyst proved completely regioselective. The cycload-
ducts 8 and 9 respectively formed (extended reaction times were
required in the case of 7) were isolated after purification by
column chromatography over silica gel in 44–66% yields
(Table 3).
1
What is remarkable about the H NMR spectra of the com-
pounds 8 is a 2.1 Hz coupling constant between the methyl
protons (2.44 ppm) and H5 (6.18 ppm) (see Table 3). The pres-
ence of a methyl group at C3, already shown on 8c by an NMR
HMQC sequence, was confirmed by X-ray diffraction on crystals
of 8a,b, allowing an unambiguous assignment (Table 3, entries
1–3†).
2,2-Dicyano-3-(4-chlorophenyl)oxirane (1c) was also reacted
with 3-phenylpropiolonitrile (10) as before to afford the expected
product 11. The reaction nevertheless proved less efficient, and
the cycloadduct 11 could not be separated from the dioxolanes
12 coming from a reaction with the aldehyde resulting from
epoxide degradation (Scheme 1).
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Table 4 Relative energies (ΔE, in kcal mol−1, relative to 1′a + 4 and 1′
a + 6) in gas phase and in toluene, and relative enthalpies (ΔH, in kcal
mol−1), entropies (ΔS, in eu) and free energies (ΔG in kcal mol−1) at
110 °C in toluene of the stationary points involved in the 32CA
reactions of CY 1′a with methyl propiolate (4) and methyl but-2-ynoate
(6)
Scheme 1 The different products obtained by the reaction of 2,2-
dicyano-3-(4-chlorophenyl)oxirane (1c) with 3-phenylpropiolonitrile
(10).
ΔE
ΔEtoluene
ΔH
4.7
6.2
−66.2
−67.3
6.4
9.8
−62.7
−64.4
ΔS
ΔG
20.9
21.9
−48.1
−48.7
24.4
26.8
−42.5
−44.6
TS1m
TS1o
CA1m
CA1o
TS2m
TS2o
2.3
4.3
−71.9
−72.6
3.6
7.9
−68.3
−69.5
4.4
6.1
−68.4
−69.5
6.3
9.8
−64.4
−66.1
−42.3
−41.0
−47.0
−48.3
−47.1
−44.2
−52.6
−51.4
Calculations
Mechanistic study of the 32CA reactions of the carbonyl ylide 1′
a with methyl propiolate (4) and methyl but-2-ynoate (6)
CA2m
CA2o
In order to explain the reactivity and regioselectivity of the
32CA reactions of the carbonyl ylide (CY) 1′a with methyl pro-
piolate (4) and methyl but-2-ynoate (6), the mechanisms of these
cycloaddition reactions were theoretically studied using DFT
methods at the B3LYP/6-31G* level.
(TS1o) and 4.3 (TS2o) kcal mol−1 higher in energy than those
associated with the most favorable channels m. These results
agree entirely with the experimentally observed regioselectivity.
In this way, a mixture of CA1m and CA1o is expected for the
32CA reaction between 1′a and 4, while for the reaction with 6
only one CA, CA2m, is expected. Experimentally, a CA1m :
CA1o 76 : 24 mixture is obtained. All these 32CA reactions are
The CY 1′a can adopt the E or Z configuration through the
restricted rotation of the C1–O2 bond. In this way, while (E)-1′a
adopts a planar rearrangement, (Z)-1′a is twisted as a conse-
quence of the hindrance between the phenyl and one cyano
group. This hindrance makes (Z)-1′a 8.6 kcal mol−1 higher in
energy than (E)-1′a. In addition, the barrier height associated
strongly exothermic: between −68.3 and −72.6 kcal mol−1
.
The B3LYP/6-31G* geometries were further optimized using
the 6-311G* and 6-311+G* basis sets. The energy results are
given in the ESI† part. A comparison of the relative energies
using the three selected basis sets indicates that there are no sig-
nificant differences. The activation energies increase slightly
with the size of the basis set, but this fact is a consequence of
the higher stabilization of CY 1′a than the TSs. Anyway, the
regioselectivity found at these 32CA reactions is kept no matter
which basis set is used.
Recent studies devoted to 32CA reactions have shown that
solvent effects in the geometry optimization have poor effects
due to the low polar character of both TSs and CAs, and of
toluene and dichloromethane solvents.12 Consequently, solvent
effects of toluene on energies were considered through single-
point energy calculations over the gas-phase optimized geome-
tries using the PCM method. Solvent effects stabilize all species
between 2 and 7 kcal mol−1 (see Table 4), with the reagents
being more stabilized than the TSs.12 Therefore, the activation
barrier for the cycloadditions increases by 2.1 (TS1m) and 2.7
(TS2m) kcal mol−1. However, solvent effects do not change the
gas phase regioselectivity. Therefore, solvent effects appear to
have little influence on these 32CA reactions.
Further thermodynamic calculations with regard to toluene
showed a similar free energy difference between each pair of
regioisomeric TSs (see Table 4). Adding thermal corrections to
energies and entropies increases the activation free energies to
20.9 (TS1m), 21.9 (TS1o), 24.4 (TS2m) and 26.8 (TS2o)
kcal mol−1. Several conclusions can be drawn from these ener-
gies: (i) these free activation energies are not very high. However,
the endergonic character of the formation of the CY 1′a, which
raises the activation free energies of these 32CA reactions
to 29.6 (TS1m) and 33.1 (TS2m) kcal mol−1, is responsible for
the high temperature demanded in these thermal reactions.7 Note
that the free energy of the CY 1′a is 8.7 kcal mol−1 above than
the corresponding epoxide;7 (ii) the presence of an electron-
with the C1–O2 bond rotation is very large, 27.1 kcal mol−1 5c
.
Consequently, only the E configuration of the CY 1′a is con-
sidered in the present study.
Due to the asymmetry of both reagents, two competitive reac-
tion channels are feasible for each 32CA reaction. They are
related to the two regioisomeric approach modes of the CY 1′a
towards the alkynes 4 and 6, named m and o (the m and o acro-
nyms, traditionally used to refer to the relative meta and ortho
positions in the benzene series, are here employed to distinguish
the cycloadduct (CA) with distant ester and nitrile functions
from that with adjacent ester and nitrile functions). Along the
channel m, the C1–C5 and C3–C4 bonds are formed, while
along the channel o, the C1–C4 and C3–C5 bonds are formed.
The two regioisomeric channels were studied. Analysis of the
stationary points associated with these 32CA reactions indicates
that they have a one-step mechanism. Therefore, two transition
states (TSs), TSxm and TSxo, and two CAs, CAxm and CAxo,
were located and characterized for each 32CA reaction (see
Scheme 2).
The two 32CA reactions present very low activation barriers:
2.3 kcal mol−1 for TS1m and 3.6 kcal mol−1 for TS2m (see
Table 4). On the other hand, the two regioisomeric TSs are 2.0
Scheme 2 32CA reactions between CY 1′a and methyl propiolate (4)
or methyl but-2-ynoate (6).
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releasing methyl group in methyl but-2-ynoate (6) increases the
free activation energy by 3.5 kcal mol−1 relative to that using
methyl propiolate (4); (iii) the regioselectivity measured as the
activation free energy difference between the two regioisomeric
TSs remains almost unaltered after the thermodynamic calcu-
involving asymmetric reagents; (iii) in the four TSs, the C–C
bond formation at the β position of 4 and 6 is slightly more
advanced than at the α position.
The polar or non-polar character of these 32CA reactions was
analyzed evaluating the CT at the four TSs. The natural charges
were shared between the CY and the alkyne frameworks. At the
TSs, the charge at the CY framework is 0.05 at TS1m, 0.02 at
TS1o, 0.00 at TS2m and −0.01 at TS2o. These negligible CTs
indicate that these 32CA reactions have a non-polar character.
lations: ΔG(TS1o–TS1m) = 1.0 kcal mol−1 and ΔG(TS2o–TS2m)
=
2.4 kcal mol−1; and (iv) these 32CA reactions are strongly exer-
gonic: between −42.5 to −48.7 kcal mol−1. Consequently, these
reactions are irreversible.
The B3LYP/6-31G* geometries of the TSs associated with the
32CA reactions between the CY 1′a and methyl propiolate (4)
and methyl but-2-ynoate (6) are given in Fig. 1, while those
obtained using the 6-311G* and 6-311+G* basis sets are given
in the ESI† part. At the TSs associated with the 32CA reaction
between the CY 1′a and methyl propiolate (4), the lengths of the
C–C forming bonds are 2.375 Å (C1–C5) and 2.505 Å (C3–C4)
at TS1m, and 2.283 Å (C3–C5) and 2.626 Å (C1–C4) at TS1o,
while those in the 32CA reaction involving methyl but-2-ynoate
(6) are 2.487 Å (C1–C5) and 2.374 Å (C3–C4) at TS2m, and
2.415 Å (C3–C5) and 2.484 Å (C1–C4) at TS2o. A comparison
of these lengths with those obtained using the 6-311G* and
6-311+G* basis sets indicates that there are no significant geo-
metrical differences.
The electronic structure of the TSs involved in the 32CA reac-
tions between the CY 1′a and methyl propiolate (4) and methyl
but-2-ynoate (6) was analyzed using the Wiberg bond order13
(BO) and charge transfer (CT) at the TSs. The extent of bond
formation at the TSs is provided by the BOs. At the TSs associ-
ated with the 32CA reaction between the CY 1′a and methyl pro-
piolate (4), the BO values of the C–C forming bonds are 0.22
(C1–C5) and 0.17 (C3–C4) at TS1m, and 0.26 (C3–C5) and
0.15 (C1–C4) at TS1o, while those in the 32CA reaction invol-
ving methyl but-2-ynoate (6) are 0.22 (C1–C5) and 0.19 (C3–
C4) at TS2m, and 0.22 (C3–C5) and 0.18 (C1–C4) at TS2o.
Several conclusions can be drawn from these values: (i) the rela-
tive low BO values found at the four TSs indicate that they have
an earlier character, in clear agreement with the very low acti-
vation energies and the high exothermic character of these pro-
cesses;14 (ii) the similar BO values of the two forming bonds at
the TSs indicate that they do not present a marked asynchronicity
in bond formation as would be expected in a polar process
Analysis based on the global reactivity indices at the ground
state of the reagents
Studies devoted to Diels–Alder and 32CA reactions have shown
that the analysis of the global indices defined within the context
of conceptual DFT15 is a powerful tool to understand the behav-
ior of polar cycloadditions.16 In Table 5, we report the static
global properties, namely, electronic chemical potential μ,
chemical hardness η, global electrophilicity ω and nucleophili-
city N of the CY 1′a and methyl propiolate (4) and methyl
but-2-ynoate (6).
The electronic chemical potential μ of methyl propiolate (4),
μ = −4.42 eV, and methyl but-2-ynoate (6), μ = −4.04 eV, is
slightly higher than that for the CY 1′a, −4.61 eV. The gaps of
electronic chemical potentials between reagents, Δμ, are below
0.6 eV. These low values do not permit to establish a tendency
for the flux of the CT along the cycloaddition, in clear agreement
with the NBO analysis at the corresponding TSs.
The CY 1′a has a high electrophilicity value, ω = 4.29 eV,
being classified as a strong electrophile in the electrophilicity
scale. On the other hand, the CY 1′a also has a very high
nucleophilicity value, N = 3.28 eV, also being classified as a
strong nucleophile in the nucleophilicity scale. Consequently, the
CY 1′a can act as a strong electrophile towards nucleophilic
species and as a strong nucleophile towards electrophilic species.
Methyl propiolate (4) and methyl but-2-ynoate (6) present low
electrophilicity values, ω = 1.52 and 1.29 eV, respectively, being
classified as moderate electrophiles. On the other hand, they
have somewhat low nucleophilicity values, N = 1.48 and
1.92 eV, respectively, being also classified as poor nucleophiles.
As expected, the methyl substitution in methyl but-2-ynoate (6)
decreases the electrophilicity and increases the nucleophilicity of
methyl propiolate (4).
Analysis of the reactivity indices indicates that although the
CY 1′a can participate in polar 32CA reactions as a consequence
of its high electrophilic and nucleophilic character, the low elec-
trophilic and nucleophilic power of methyl propiolate (4) and
methyl but-2-ynoate (6) prevent their participation in polar
Table 5 Electronic chemical potential (μ, in au), chemical hardness
(η, in au), global electrophilicity (ω, in eV) and global nucleophilicity
(N, in eV) values of CY 1′a and methyl propiolate (4) and methyl but-2-
ynoate (6)
μ
η
ω
N
1′a
4
6
−4.61
−4.42
−4.04
2.47
6.43
6.32
4.29
1.52
1.29
3.28
1.48
1.92
Fig. 1 Transition structures involved in the reactions between CY 1′a
and methyl propiolate (4) and methyl but-2-ynoate (6) (distances are
given in Å).
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Table 6 Valence basin populations N calculated from the ELF of some
selected points of the IRC associated with the most favorable
regioisomeric channel of the 32CA reaction between CY 1′a and methyl
propiolate (4). The CT is also included
cycloadditions. The behavior of the alkynes 4 and 6 could be
responsible for the low CT observed at the corresponding TSs.
ELF topological analysis of the 32CA reaction between the CY
1′a and methyl propiolate (4)
Recent theoretical studies have shown that the topological analy-
sis of the ELF along the reaction path associated with a cyclo-
addition is a valuable tool for understanding the bonding
changes along the reaction path.17 Consequently, a topology
analysis of the ELF of some selected points along the most
favorable reaction path associated with the 32CA reaction
between the CY 1′a and methyl propiolate (4) was performed in
order to understand the bond-formation in these 32CA reactions.
The N populations of the most relevant ELF valence basins are
listed in Table 6. A schematic picture of the attractor positions
and atom numbering is shown in Fig. 2.
1′a + 4
TS1m
P1
P2
CA1m
d1(C1–C5)
d2(C3–C4)
CT(NBO)
CT(ELF)
V(C1,O2)
V(O2)
2.375
2.505
0.05
0.06
1.54
3.95
2.075
2.255
0.07
0.07
1.44
4.38
1.767
1.922
0.07
0.08
1.34
2.49
2.26
1.41
2.17
1.94
1.96
1.523
1.515
1.69
3.57
1.24
2.59
2.45
1.22
2.05
1.84
1.74
V′(O2)
V(O2,C3)
V(C3,C6)
V(C4,C5)
V′(C4,C5)
V(C1)
V′(C1)
V(C3)
V(C4)
V(C5)
V(C1,C5)
V(C3,C4)
2.14
2.79
2.70
2.70
0.59
0.58
1.91
2.69
2.51
2.47
0.90
1.62
2.35
2.17
2.17
1.05
ELF analysis of the CY 1′a shows two disynaptic basins
V(C1,O2) and V(O2,C3), whose electronic populations integrate
1.69e and 2.14e, respectively, one monosynaptic basin V(O2)
integrating 3.57e, and two monosynaptic basins V(C1) and
V′(C1), integrating 1.17e. Recently, we studied the non-polar
32CA reaction between the CY 13 and tetramethylethylene (14)
(see Scheme 3).17d ELF analysis of the CY 13 showed two pairs
of monosynaptic basins V(Cx) and V′(Cx) at each C2 and C2′
carbon, integrating ca. 1.0e each pair, and one monosynaptic
basin V(O1) integrating 3.58e. The high reactivity of the CY 13
towards unactivated tetramethylethylene (14) was attributed to
its pseudodiradical electronic structure, which allows for the
C–C bond formation. Note that the activation enthalpy associated
0.46
0.71
0.42
0.35
1.79
1.69
1.97
2.04
with this non-polar 32CA reaction was only 4.7 kcal mol−1 17d
.
The absence of the two monosynaptic basins at the C3 carbon of
the CY 1′a can be explained by a delocalization of the electron
density of this pseudodiradical center at the adjacent phenyl
group. This delocalization is supported by the changes of elec-
tron density of the disynaptic basin V(C3,C6) along the IRC,
which decreases from 2.79e in CY 1′a to 2.05e in CA1m.
Scheme 3
Fig. 2 ELF attractors at selected points of the IRC associated with the
32CA reaction between CY 1′a and methyl propiolate (4).
On the other hand, methyl propiolate (4) has two disynaptic
basins V(C4,C5) and V′(C4,C5), integrating 5.40e. These disy-
naptic basins account for the C4–C5 triple bond drawn in the
Lewis structure of methyl propiolate (4).
Along the 32CA pathway, the ELF analysis of TS1m, d1 =
2.375 Å and d2 = 2.505 Å, shows that while the two monosynap-
tic basins V(C1) and V′(C1) have merged into one monosynaptic
basin V(C1), integrating 0.90e, a new monosynaptic basin
V(C4), integrating 0.35e, has been created at the C4 carbon of
methyl propiolate (4). Simultaneously, the two disynaptic basins
V(C4,C5) and V′(C4,C5) belonging to the C4–C5 triple bond
region of 4 have been depopulated by ca. 0.40e. At this point of
the IRC, the CT is very low, 0.05e. This low value indicates that
this cycloaddition has no polar character. Unlike polar cycloaddi-
tions in which monosynaptic basins appear at the most electro-
philic center of the electrophile as a consequence of the CT
which takes place along the nucleophilic attack, in the present
non-polar cycloaddition, the monosynaptic basin V(C4) appears
as a consequence of the internal electron reorganization that
takes place at the C4–C5 triple bond region along the reaction
path.
At P1, d1 = 2.075 Å and d2 = 2.255 Å, while the monosynap-
tic basin V(C1) has slightly increased its population, the mono-
synaptic basin V(C4) has reached 0.71e. Additionally, at this
point of the IRC two monosynaptic basins V(C3) and V(C5),
8438 | Org. Biomol. Chem., 2012, 10, 8434–8444
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What is the origin of the regioselectivity in these non-polar
32CA reactions?
integrating 0.46e and 0.42e respectively, have been created at the
C3 carbon of the CY 1′a and at C5 carbon of 4. Simultaneously,
the C4–C5 triple bond region has been depopulated by 0.64e. At
P2, d1 = 1.767 Å and d2 = 1.922 Å, the four monosynaptic
basins V(C1) and V(C5), and V(C3) and V(C4), have merged
into two new disynaptic basins, V(C1,C5) and V(C3, C4), which
integrate 1.79e and 1.69e, respectively. Consequently, at this
point of the IRC, the two new C1–C5 and C3–C4 σ bonds have
already been formed. At P2, while the populations of the two
disynaptic basins V(C4,C5) and V′(C4,C5) have decreased to
1.94e and 1.96e, the monosynaptic basin V(O2) present in the
CY 1′a has split into two monosynaptic basins V(O2) and V′(O2),
integrating 2.49e and 2.26e. Finally, CA1m, d1 = 1.523 Å
and d2 = 1.515 Å, presents a similar bonding pattern to that at
P2. As shown in Table 6, only slight changes in the basin popu-
lations take place at the end of the reaction.
The ELF bonding analysis at TS1m indicates that the main
change in the electronic structure of methyl propiolate (4) is
associated with the formation of a C4 pseudoradical center.
Note that at the CY 1′a, only the fusion of the two monosynaptic
basins V(C1) and V′(C1) into the monosynaptic basin V(C1)
takes place. This change is associated with the depopulation in
electron density at the C4–C5 triple bond region. This behavior
together with the very low CT at TS1m, 0.06e (ELF) and 0.05
(NBO), suggests a non-polar 32CA reaction with a pseudo-
diradical character. Recently, we established that the high
reactivity of CYs in non-polar processes can be associated with
their pseudodiradical character, which enables the reaction to
take place through an unappreciable barrier.17d
Finally, ELF bonding analysis at the C1–O2–C3 framework of
the CY 1′a along the 32CA reaction shows that while the elec-
tron density of the monosynaptic basins V(O2) and V′(O2)
increases from 3.57e in the CY 1′a to 5.04 e in CA1m, the elec-
tron density of the disynaptic basins V(C1,O2) and V(O2,C3)
decreases from 3.83e in the CY 1′a to 2.46e in CA1m. This be-
havior, which is similar to that found in the non-polar 32CA
reaction between the CY 13 and tetramethylethylene (14) in
Scheme 3,17d indicates that the O2 lone pairs of the CY 1′a do
not participate in the C–C bond formation in the 32CA reaction;
while in the CY 1′a these O2 lone pairs are partially delocated
in the pseudoradical C1 and C3 centers, in CA1m they are
mainly located at the O2 oxygen as a consequence of the satur-
ation of the C1 and C3 carbons after the C–C bond formations.
This behavior allows for the establishment that these 32CA reac-
tions may be electronically classified as [2n + 2π] processes,17c,d
in which only the two electrons of the HOMO of the CY 1′a
and the two electrons of the HOMO − 1 of methyl propiolate (4)
participate in the 32CA reaction (see Fig. 3).
While Diels–Alder reactions present a high regioselectivity,
which increases with the polar character of the reaction,18 32CA
reactions present a low regioselectivity, which also depends on
polarity. Thus, it is expected that these non-polar 32CA reactions
will have a poor regioselectivity. However, both experimental
and theoretical calculations show that both reactions are regio-
selective. Analyses of the local reactivity indices indicate that the
C1 carbon of the CY 1′a is the most nucleophilic center,7 and
that the β conjugated C5 position of methyl propiolate (4) and
methyl but-2-ynoate (6) is the most electrophilic center of these
molecules. Therefore, although the polar analysis explains the
observed regioselectivity, the bonding pattern involved in polar
cycloadditions cannot rule in these non-polar 32CA reactions.19
ELF analysis of the electronic structures of the four TSs
involved in these non-polar 32CA reactions allows us to obtain
some interesting information. For simplicity, only the ELF attrac-
tors of the four TSs are given in Fig. 4. The four TSs show two
monosynaptic basins, the V(C1) and the V(C4) at the regio-
isomeric TS1m and TS2m, and the V(C1) and the V(C5) at the
regioisomeric TS1o and TS2o. Therefore, the four TSs share the
presence of the monosynaptic basin V(C1), which is already
present in the CY 1′a with similar population, and the mono-
synaptic basins V(C4) in channels m and the V(C5) in channels o,
which are created along the reaction. Interestingly, in the four
TSs, the first monosynaptic basin at the acetylenic system
appears at the opposite carbon of the CY, regardless of the carbo-
nyl group position. Note that in a polar cycloaddition, these
basins appear always at the β conjugated position, which corres-
pond with the most electrophilic center of these acetylene
derivatives.19 Consequently, we can associate the relative stabi-
lity of the two pairs of regioisomeric TSs with the relative stabi-
lity of the corresponding pseudodiradical species formed on
going to the corresponding TS. Unlike the polar cycloadditions
in which the formation of the monosynaptic basins takes place
firstly at the β conjugated position, in these non-polar 32CA
Fig. 4 ELF attractors at the TSs involved in the non-polar 32CA reac-
tions between CY 1′a and methyl propiolate (4) and methyl but-2-
ynoate (6).
Fig. 3 HOMO of CY 1′a and the two electrons of HOMO − 1 of
methyl propiolate (4).
This journal is © The Royal Society of Chemistry 2012
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reactions the formation of the monosynaptic basin at the α posi-
tion appears to be favored over the β one. This finding could
explain the larger regioselectivity found in the 32CA reaction
using methyl but-2-ynoate (6) than that with methyl propiolate
(4). The presence of the electron-releasing methyl group on C5
carbon of but-2-ynoate (6) favors the formation of monosynaptic
basin V(C4) in TS2m with respect to TS1m. This behavior is
supported by the larger population of the monosynaptic basin
V(C4) in TS2m, 0.58e, than that in TS1m, 0.35e. Note that in
both TSs, the monosynaptic basin V(C1) presents the same
population, 0.90e.
dihydrofuran-2,2-dicarbonitrile 3 and methyl 2,2-dicyano-5-(4-
substituted phenyl)-(2H,5H)-dihydrofuran-4-carboxylate 5′ only
dominate using phenylacetylene (2) and methyl propiolate (4),
respectively, the use of methyl but-2-ynoate (6) and methyl
3-phenylpropiolate (7) led to only one regioisomer, the methyl
5-(4-substituted phenyl)-2,2-dicyano-(2H,5H)-dihydrofuran-4-
carboxylates 8 and 9, respectively methylated or phenylated
at C3. The different observed regioisomeric ratios using methyl
propiolate (4) and methyl but-2-ynoate (6) in the reactions with
the CY 1′a were explained by theoretical calculations.
Despite the high electrophilic and nucleophilic character of
the CY 1′a, the low electrophilic and nucleophilic character of
the alkynes 4 and 6 causes these 32CA reactions to take place
through a non-polar mechanism via TSs with a pseudodiradical
character. In spite of the low activation energy associated with
these non-polar 32CA reactions, the endothermic character
associated with the formation of the CY 1′a was found to be
responsible for the high temperature required to carry out these
thermal reactions. Finally, analysis of the bonding changes along
these 32CA reactions allows for the classification of these non-
polar cycloadditions as [2n + 2π] processes.
Pharmacology
Applying the agar plate diffusion technique,20 the newly syn-
thesized compounds 3a, 5′c and 9c were screened in vitro for
their bactericidal activity against Gram positive bacteria (Staphy-
lococcus aureus) and Gram negative bacteria (Escherichia coli
and Pseudomonas aeroginosa), and for their fungicidal activity
towards Fusarium oxysporium, Aspergillus niger and Candida
albicans (Table 7). All the compounds tested showed moderate
bactericidal activities against Staphylococcus aureus, Escheri-
chia coli and Pseudomonas aeroginosa compared to that of
ciprofloxacin as a reference drug. The compounds tested showed
moderate fungicidal activities towards Fusarium oxysporium and
Aspergillus niger compared to that of nystin as a reference,
except the compound 5′c that showed significant activities, in
particular against Fusarium oxysporium. Only the compound 5′c
showed a moderate activity against Candida albicans.
The compounds 3a,b, 5′c and 9c were also tested against a
human liver carcinoma cell line (HEPG2), and 3b against human
breast (MCF7) and cervix (HELA) carcinoma cell lines
(Table 8). Moderate cytotoxic activities were observed for all the
compounds tested, compared to a reference drug (doxorubicin),
except in the case of 3b, for which activities close to those of
doxorubicin were observed. The difference in the value of IC50
between the two compounds 3a and 3b may be due to the pres-
ence of the chloro group in 3b, a substituent that can affect the
biological activity of the compounds.21
Experimental
Syntheses: general methods
Liquid chromatography separations were achieved on silica gel
Merck–Geduran Si 60 (40–63 μm). Petrol refers to petroleum
ether (bp 40–60 °C). Melting points were measured on a Kofler
apparatus. Nuclear magnetic resonance spectra were acquired
using a Bruker AC-300 spectrometer (300 MHz and 75 MHz for
1H and 13C respectively). 1H chemical shifts (δ) are given in
Table 8 In vitro cytotoxic activity (IC50)a of the compounds 3a,b, 5′c,
9c, and doxorubicin against carcinoma cell lines
HEPG2
MCF7
HELA
Entry
Compound
(μg mL−1
)
(μg mL−1
)
(μg mL−1
)
1
2
3
4
5
3a
3b
5′c
9c
2.88
0.67
2.98
3.34
0.60
—
0.74
—
—
0.70
—
0.89
—
—
0.85
Doxorubicin
Conclusions
a IC50 is defined as the concentration which results in a 50% decrease in
the cell number as compared with that of the control structures in the
absence of an inhibitor.
Thus, substituted 2,5-dihydrofurans were synthesized by the
32CA reaction between carbonyl ylides generated from epoxides
and alkynes. While 3-phenyl-5-(4-substituted phenyl)-(2H,5H)-
Table 7 Bactericidal and fungicidal activitya of the compounds 3a, 5′c, 9c, and ciprofloxacin and nystin
Staphylococcus
aureus
Escherichia
coli
Pseudomonas
aeroginosa
Fusarium
oxysporium
Aspergillus
niger
Candida
albicans
Entry
Compound
1
2
3
4
5
3a
5′c
9c
19 (++)
27 (+++)
18 (++)
++++
17 (++)
15 (++)
17 (++)
++++
17 (++)
22 (++)
16 (++)
++++
—
19 (++)
43 (++++)
16 (++)
—
20 (++)
27 (+++)
18 (++)
—
—
18 (++)
—
—
Ciprofloxacin
Nystin
—
—
++++
++++
++++
a The diameters of zones of inhibition are given in mm. Stock solution: 5 μg in 1 mL of DMF. 0.1 mL of stock solution in each hole of each paper
disk. +: <15 mm; ++: 15–24 mm; +++: 25–34 mm; ++++: 35–44 mm, etc.
8440 | Org. Biomol. Chem., 2012, 10, 8434–8444
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ppm relative to the solvent residual peak, and 13C chemical
shifts relative to the central peak of the solvent signal. NOESY,
HMBC and HMQC experiments were performed on an Avance
500 spectrometer (500 MHz and 125 MHz for 1H and 13C,
respectively). High resolution mass spectra measurements were
recorded at the Centre Régional de Mesures Physiques de
l’Ouest (CRMPO) in Rennes. Oxiranes were prepared according
to the described procedures.9 Toluene was dried before use.
Reactions were performed under dry argon.
General procedure 3. A mixture of epoxide (2 mmol) and
methyl propiolate (0.67 g, 8 mmol in the case of 1a,b; 0.16 g,
2 mmol in the case of 1c) in anhydrous toluene (30 mL) was
heated at reflux under Ar for 48 h (1a,b) or 24 h (1c). The
mixture was then evaporated to dryness and the product isolated
by column chromatography over silica gel (eluent: 10 : 90
AcOEt–petrol in the case of 1a,b; 20 : 80 with 1c).
General procedure 4. A mixture of epoxide (2 mmol), methyl
propiolate (0.67 g, 8 mmol in the case of 1a,b; 0.16 g, 2 mmol
in the case of 1c) and InCl3 (40 mg, 0.2 mmol) in anhydrous
toluene (30 mL) was heated at reflux under Ar for 36 h (1a,b) or
20 h (1c). The mixture was then evaporated to dryness and the
product isolated by column chromatography over silica gel
(eluent: 10 : 90 AcOEt–petrol in the case of 1a,b; 20 : 80
with 1c).
General procedure 1. A mixture of epoxide (2 mmol) and
phenylacetylene (1.0 g, 10 mmol) in anhydrous toluene (30 mL)
was heated at reflux under Ar for 40 h. The mixture was then
evaporated to dryness and the product isolated by column
chromatography over silica gel (eluent: 25 : 75 CH2Cl2–petrol).
Methyl 2,2-dicyano-5-phenyl-(2H,5H)-dihydrofuran-3-carboxy-
late (5a). Yield: 12% (general procedure 3). Yellow oil. 1H
NMR (300 MHz, CDCl3): 3.95 (s, 3H), 6.27 (d, 1H, J =
1.8 Hz), 7.26 (d, 1H, J = 1.8 Hz), 7.29–7.32 (m, 3H), 7.42–7.45
(m, 2H). 13C NMR (75 MHz, CDCl3): 53.4, 72.4, 91.7, 112.0,
112.3, 126.9 (2C), 128.1, 130.2 (2C), 130.2, 134.6, 146.7,
159.1. HRMS (ESI): calcd for C14H10N2O3 (M+˙) 254.0589,
found 254.0592.
Methyl 2,2-dicyano-5-phenyl-(2H,5H)-dihydrofuran-4-carboxy-
late (5′a). Yield: 40% (general procedure 3), 58% (general pro-
cedure 4). White powder, mp 102 °C. 1H NMR (300 MHz,
CDCl3): 3.73 (s, 3H), 6.24 (d, 1H, J = 2.1 Hz), 6.78 (d, 1H, J =
2.1 Hz), 7.32–7.35 (m, 2H), 7.41–7.43 (m, 3H). 13C NMR
(75 MHz, CDCl3): 53.0, 72.3, 91.1, 111.6, 111.8, 127.6 (2C),
128.7, 129.1 (2C), 130.1, 135.1, 142.9, 160.2. HRMS (ESI):
calcd for C14H10N2O3 (M+˙) 254.0589, found 254.0593.
Methyl 5-(4-chlorophenyl)-2,2-dicyano-(2H,5H)-dihydrofuran-3-
carboxylate (5b). Yield: 10% (general procedure 3). Yellow oil.
1H NMR (300 MHz, CDCl3): 3.96 (s, 3H), 6.24 (d, 1H, J =
1.8 Hz), 7.23 (d, 1H, J = 1.8 Hz), 7.24–7.27 (m, 2H), 7.40–7.43
(m, 2H). 13C NMR (75 MHz, CDCl3): 54.5, 72.4, 90.8, 111.9,
112.2, 128.3 (2C), 128.6, 129.8 (2C), 133.1, 136.3, 146.0,
159.0. HRMS (APCI/ASAP): calcd for C14H835ClN2O3
[(M − H)+˙] 287.0218, found 287.0222.
General procedure 2. A mixture of epoxide (2 mmol),
phenylacetylene (0.80 g, 8 mmol) and InCl3 (40 mg, 0.2 mmol)
in anhydrous toluene (30 mL) was heated at reflux under Ar for
29 h (1a), 27 h (1b) and 20 h (1c). The mixture was then evapor-
ated to dryness and the product isolated by column chromato-
graphy over silica gel (eluent: 25 : 75 CH2Cl2–petrol).
3,5-Diphenyl-(2H,5H)-dihydrofuran-2,2-dicarbonitrile (3a). Yield:
40% (general procedure 1), 60% (general procedure 2). White
1
powder, mp 133 °C. H NMR (300 MHz, CDCl3): 6.25 (d, 1H,
J = 1.8 Hz), 6.65 (d, 1H, J = 1.8 Hz), 7.36–7.39 (m, 2H),
7.43–7.48 (m, 3H), 7.48–7.50 (m, 3H), 7.65–7.68 (m, 2H). 13C
NMR (75 MHz, CDCl3): 73.8, 91.6, 113.1, 113.2, 126.8 (2C),
127.0 (2C), 127.5, 129.3 (2C), 129.5 (2C), 129.8, 130.5, 131.0,
134.6, 136.5. HRMS (ESI): calcd for C18H12N2O (M+˙)
272.0842, found 272.0842.
5-(4-Chlorophenyl)-3-phenyl-(2H,5H)-dihydrofuran-2,2-dicarbo-
nitrile (3b). Yield: 52% (general procedure 1), 64% (general pro-
cedure 2). Yellow powder, mp 85 °C. 1H NMR (300 MHz,
CDCl3): 6.22 (d, 1H, J = 1.8 Hz), 6.62 (d, 1H, J = 1.8 Hz), 7.30
(d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.46–7.50 (m,
3H), 7.63–7.67 (m, 2H). 13C NMR (75 MHz, CDCl3): 73.7,
90.7, 112.8, 113.1, 126.8 (2C), 127.2, 128.4 (2C), 129.5 (2C),
129.6 (2C), 130.5, 130.7, 134.9, 135.0, 135.7. HRMS (ESI):
calcd for C18H1135ClN2O (M+˙) 306.0576, found 306.0455.
Methyl 5-(4-chlorophenyl)-2,2-dicyano-(2H,5H)-dihydrofuran-4-
carboxylate (5′b). Yield: 54% (general procedure 3), 57%
(general procedure 4). White powder, mp 105 °C. 1H NMR
(300 MHz, CDCl3): 3.75 (s, 3H), 6.21 (d, 1H, J = 2.1 Hz), 6.78
(d, 1H, J = 2.1 Hz), 7.26–7.29 (m, 2H), 7.39–7.41 (m, 2H). 13C
NMR (75 MHz, CDCl3): 53.1, 72.3, 90.3, 111.4, 111.7, 128.9,
129.0 (2C), 129.5 (2C), 133.7, 136.2, 142.6, 160.0. HRMS
(APCI/ASAP): calcd for C14H835ClN2O3 [(M − H)+˙] 287.0218,
found 287.0219.
5-(4-Chlorophenyl)-4-phenyl-(2H,5H)-dihydrofuran-2,2-dicarbo-
nitrile (3′b). Yield: 12% (general procedure 1). Pale yellow oil.
1H NMR (300 MHz, CDCl3): 6.33 (d, 1H, J = 2.1 Hz), 6.41 (d,
1H, J = 2.1 Hz), 7.26–7.29 (m, 2H), 7.29–7.32 (m, 3H),
7.34–7.37 (m, 4H). 13C NMR (75 MHz, CDCl3): 72.6, 91.1,
112.7, 113.0, 127.3, 127.5 (2C), 129.1, 129.2 (2C), 129.6 (2C),
129.6, 129.7 (2C), 130.9, 134.6, 136.1. HRMS (ESI): calcd for
C18H1135ClN2O (M+˙) 306.0576, found 306.0459.
5-(4-Methoxyphenyl)-3-phenyl-(2H,5H)-dihydrofuran-2,2-dicarbo-
nitrile (3c). Yield: 50% (general procedure 1), 60% (general pro-
cedure 2). Yellow powder, mp 118 °C. 1H NMR (300 MHz,
CDCl3): 3.83 (s, 3H), 6.20 (d, 1H, J = 1.8 Hz), 6.62 (d, 1H, J =
1.8 Hz), 6.94–6.97 (m, 2H), 7.27–7.31 (m, 2H), 7.47–7.50 (m,
3H), 7.64–7.67 (m, 2H). 13C NMR (75 MHz, CDCl3): 55.5,
73.5, 91.4, 113.1, 113.3, 114.6 (2C), 126.8 (2C), 127.6, 128.5,
128.8 (2C), 129.5 (2C), 130.5, 131.0, 134.6, 160.8. HRMS
(ESI): calcd for C19H14N2O2 [(M + Na)+˙] 302.0953, found
302.0953.
Methyl 2,2-dicyano-5-(4-methoxyphenyl)-(2H,5H)-dihydrofuran-
3-carboxylate (5c). Yield: 11% (general procedure 3), 8%
(general procedure 4). Yellow oil. H NMR (300 MHz, CDCl3):
3.82 (s, 3H), 3.96 (s, 3H), 6.22 (d, 1H, J = 1.5 Hz), 6.93–6.96
(m, 2H), 7.20–7.23 (m, 2H), 7.24 (d, 1H, J = 1.5 Hz). 13C NMR
(75 MHz, CDCl3): 53.4, 55.5, 72.0, 91.5, 112.1, 112.4, 114.8
(2C), 126.4, 128.2, 128.8 (2C), 146.7, 159.2, 161.1. NMR
HMQC sequences performed on 5c showed relationship between
H4 and C5 (see Table 2). HRMS (ESI): calcd for C15H12N2O4
(M+˙) 284.0689, found 284.0683.
1
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Methyl 2,2-dicyano-5-(4-methoxyphenyl)-(2H,5H)-dihydrofuran-
4-carboxylate (5′c). Yield: 65% (general procedure 3), 67%
(general procedure 4). Yellow oil. H NMR (300 MHz, CDCl3):
3.71 (s, 3H), 3.79 (s, 3H), 6.19 (d, 1H, J = 2.1 Hz), 6.77 (d, 1H,
J = 2.1 Hz), 6.91–6.94 (m, 2H), 7.23–7.26 (m, 2H). 13C NMR
(75 MHz, CDCl3): 52.9, 55.4, 71.9, 90.8, 111.6, 111.9, 114.5
(2C), 127.1, 128.5, 129.1 (2C), 142.7, 160.2, 160.8. NMR
HMQC sequences performed on 5′c showed relationship
between the phenyl protons and the carbonyl group. HRMS
(ESI): calcd for C15H12N2O4 (M+˙) 284.0689, found 284.0689.
(s, 1H), 7.44–7.46 (m, 5H), 7.52–7.56 (m, 3H), 7.60–7.63
(m, 2H). 13C NMR (75 MHz, CDCl3): 52.6, 76.9, 92.2,
112.0, 112.2, 127.0, 127.7 (2C), 128.8 (2C), 129.1 (2C), 129.2
(2C), 130.1, 131.1, 135.7, 136.0, 140.2, 161.1. HRMS (APCI/
ASAP): calcd for C20H13N2O3 [(M − H)+˙] 329.0920, found
329.0924.
1
Methyl 5-(4-chlorophenyl)-2,2-dicyano-3-phenyl-(2H,5H)-dihy-
drofuran-4-carboxylate (9b). Yield: 47% (general procedure 6).
1
White powder, mp 142 °C. H NMR (300 MHz, CDCl3): 3.53
(s, 3H), 6.36 (s, 1H), 7.35–7.38 (m, 2H), 7.42–7.45 (m, 2H),
7.50–7.60 (m, 5H). 13C NMR (75 MHz, CDCl3): 52.7, 76.7,
91.4, 111.8, 112.1, 126.8, 128.8 (2C), 129.1 (2C), 129.2 (2C),
129.5 (2C), 131.2, 134.3, 135.5, 136.2, 140.7, 161.0. HRMS
General procedure 5. A mixture of epoxide (2 mmol) and
methyl but-2-ynoate (2.1 g, 22 mmol in the case of 1a,b; 1.6 g,
16 mmol in the case of 1c) in anhydrous toluene (30 mL) was
heated at reflux under Ar for 48 h (1a,b) or 24 h (1c). The
mixture was then evaporated to dryness and the product isolated
by column chromatography over silica gel (eluent: 5 : 95
AcOEt–petrol in the case of 1a,b; 10 : 90 with 1c) followed by
recrystallization in CH2Cl2.
(APCI/ASAP): calcd for C20H1235ClN2O3 [(M
363.0531, found 363.0526.
−
H)+˙]
Methyl 2,2-dicyano-5-(4-methoxyphenyl)-3-phenyl-(2H,5H)-dihy-
drofuran-4-carboxylate (9c). Yield: 66% (general procedure 6).
1
Yellow oil. H NMR (300 MHz, CDCl3): 3.53 (s, 3H), 3.83 (s,
3H), 6.35 (s, 1H), 6.95–6.98 (m, 2H), 7.34–7.37 (m, 2H),
7.51–7.55 (m, 3H), 7.60–7.63 (m, 2H). 13C NMR (75 MHz,
CDCl3): 52.6, 55.4, 76.5, 91.9, 112.1, 112.2, 114.5 (2C), 127.0,
127.6, 128.7 (2C), 129.0 (2C), 129.2 (2C), 131.0, 135.9, 139.9,
160.9, 161.2. HRMS (ESI): calcd for C12H16N2O4 (M+˙)
360.1002, found 360.1002.
Methyl 2,2-dicyano-3-methyl-5-phenyl-(2H,5H)-dihydrofuran-4-
carboxylate (8a). Yield: 66% (general procedure 5). Yellow
1
powder, mp 83 °C. H NMR (300 MHz, CDCl3): 2.44 (d, 3H, J
= 2.10 Hz), 3.68 (s, 3H), 6.20 (q, 1H, J = 2.10 Hz), 7.28–7.31
(m, 2H), 7.39–7.41 (m, 3H). 13C NMR (75 MHz, CDCl3): 11.2,
52.5, 77.2, 92.2, 111.9, 112.0, 127.7 (2C), 129.0 (2C), 129.9,
134.1, 136.1, 140.4, 161.4. HRMS (APCI/ASAP): calcd for
C15H11N2O3 [(M − H)+˙] 267.0764, found 267.0765.
Crystallography
Methyl 5-(4-chlorophenyl)-2,2-dicyano-3-methyl-(2H,5H)-dihy-
drofuran-4-carboxylate (8b). Yield: 62% (general procedure 5).
White powder, mp 105 °C. H NMR (300 MHz, CDCl3): 2.45
(d, 3H, J = 2.10 Hz), 3.70 (s, 3H), 6.18 (q, 1H, J = 2.10 Hz),
7.23–7.26 (m, 2H), 7.37–7.40 (m, 2H). 13C NMR (75 MHz,
CDCl3): 11.2, 52.6, 77.1, 91.3, 111.7, 111.9, 129.0 (2C), 129.3
(2C), 133.7, 134.6, 135.9, 140.8, 161.2. HRMS (APCI/ASAP):
calcd for C15H1035ClN2O3 [(M − H)+˙] 301.0374, found
301.0375.
Single crystals suitable for X-ray diffraction were grown after
slow evaporation (several days at room temperature) of solutions
of 3a, 3b and 3c in CH2Cl2. The samples were studied with
graphite monochromatized MoKα radiation (λ = 0.71073 Å).
X-ray diffraction data were collected at T = 100(2) K for 3a,b, at
T = 150(2) K for 3c, and at T = 200(2) K for 5′a, 5b, 8a,b, using
an APEXII Bruker-AXS diffractometer (3a–c, 5′a, 5b, 8b) or a
KappaCCD diffractometer (8a). The structure was solved by
direct methods using the SIR97 program,22 and then refined with
full-matrix least-squares methods based on F2 (SHELX-97)23
with the aid of the WINGX program.24 All non-hydrogen atoms
were refined with anisotropic atomic displacement parameters. H
atoms were finally included in their calculated positions. Mol-
ecular diagrams were generated by ORTEP-3 (version 1.08)25
and furnished as ESI.†
1
Methyl 2,2-dicyano-5-(4-methoxyphenyl)-3-methyl-(2H,5H)-dihy-
drofuran-4-carboxylate (8c). Yield: 44% (general procedure 5).
1
Yellow oil. H NMR (300 MHz, CDCl3): 2.43 (d, 3H, J = 2.10
Hz), 3.67 (s, 3H), 3.79 (s, 3H), 6.16 (q, 1H, J = 2.10 Hz),
6.89–6.92 (m, 2H), 7.21–7.24 (m, 2H). 13C NMR (75 MHz,
CDCl3): 11.1, 52.4, 55.3, 76.8, 91.8, 111.9, 112.1, 114.3 (2C),
128.1, 129.0 (2C), 134.0, 140.0, 160.7, 161.4. An NMR HMQC
sequence performed on 8c showed a relationship between the
methyl group protons connected to the dihydrofuran ring and the
nitrile functions, in accordance with a methyl at C3 (see
Table 3). HRMS (ESI): calcd for C16H14N2O4 (M+˙) 298.0846,
found 298.0848.
Crystal data for 3a. C18H12N2O, M = 272.30, monoclinic,
P21, a = 7.7576(3), b = 6.0070(2), c = 14.7572(6) Å, β = 93.710
(2)°, V = 686.24(4) Å3, Z = 2, d = 1.32 g cm−3, μ =
0.083 mm−1. A final refinement on F2 with 1721 unique intensi-
ties and 190 parameters converged at wR(F2) = 0.067 (R(F) =
0.0275) for 1649 observed reflections with I > 2σ(I).
General procedure 6. A mixture of epoxide (2 mmol) and
methyl 3-phenylpropiolate (0.32 g, 2 mmol) in anhydrous
toluene (30 mL) was heated at reflux under Ar for 96 h (1a,b) or
55 h (1c). The mixture was then evaporated to dryness and the
product isolated by column chromatography over silica gel
(eluent: 5 : 95 AcOEt–petrol in the case of 1a,b; 10 : 90 with 1c)
followed by recrystallization in CH2Cl2.
Crystal data for 3b. 2(C18H11ClN2O), M = 613.48, monocli-
nic, P21/a, a = 11.0917(5), b = 17.5158(6), c = 16.2080(6) Å, β
= 109.615(2)°, V = 2966.2(2) Å3, Z = 4, d = 1.37 g cm−3, μ =
0.26 mm−1. A final refinement on F2 with 6660 unique intensi-
ties and 398 parameters converged at wR(F2) = 0.131 (R(F) =
0.0449) for 6009 observed reflections with I > 2σ(I).
ˉ
Methyl 2,2-dicyano-3,5-diphenyl-(2H,5H)-dihydrofuran-4-carbox-
ylate (9a). Yield: 60% (general procedure 6). Yellow powder,
mp 85 °C. 1H NMR (300 MHz, CDCl3): 3.53 (s, 3H), 6.40
Crystal data for 3c. C19H14N2O2, M = 302.32, triclinic, P1,
a = 7.446(4), b = 7.670(3), c = 15.675(11) Å, α = 97.60(4),
β = 91.12(3), γ = 118.99(2)°, V = 772.5(7) Å3, Z = 2, d =
8442 | Org. Biomol. Chem., 2012, 10, 8434–8444
This journal is © The Royal Society of Chemistry 2012

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1.30 g cm−3, μ = 0.086 mm−1. A final refinement on F2 with
3395 unique intensities and 211 parameters converged at
wR(F2) = 0.2758 (R(F) = 0.0897) for 2690 observed reflections
with I > 2σ(I).
the IRC. All calculations were carried out with the Gaussian 09
suite of programs.36
The global electrophilicity index,37 ω, is given by the follow-
ing simple expression, ω = (μ2/2η), in terms of the electronic
chemical potential μ and the chemical hardness η. Both quan-
tities may be approached in terms of the one electron energies of
the frontier molecular orbital HOMO and LUMO, εH and εL, as
μ ≈ (εH + εL)/2 and η ≈ (εL − εH), respectively.38 Recently, we
have introduced an empirical (relative) nucleophilicity index,39
N, based on the HOMO energies obtained within the Kohn–
Crystal data for 5′a. C14H10N2O3, M = 254.24, orthorhombic,
P212121, a = 6.355(1), b = 8.010(1), c = 24.798(3) Å, V =
1262.4(3) Å3, Z = 4, d = 1.34 g cm−3, μ = 0.096 mm−1. A final
refinement on F2 with 2876 unique intensities and 173 para-
meters converged at wR(F2) = 0.0921 (R(F) = 0.0391) for 2380
observed reflections with I > 2σ(I).
Sham scheme,40 and defined as N = EHOMO(Nu) − EHOMO
-
(TCE). The nucleophilicity is referred to TCE, because it pre-
sents the lowest HOMO energy in a large series of molecules
already investigated in the context of polar cycloadditions. This
choice allows us conveniently to handle a nucleophilicity scale
of positive values.39
Crystal data for 5b. C14H9ClN2O3, M = 288.68, monoclinic,
P21/c, a = 11.0681(3), b = 9.2126(3), c = 13.3847(3) Å, β =
90.0100(10)°, V = 1364.78(7) Å3, Z = 4, d = 1.40 g cm−3, μ =
0.288 mm−1. A final refinement on F2 with 3101 unique intensi-
ties and 182 parameters converged at ωR(F2) = 0.0906 (R(F) =
0.0372) for 2394 observed reflections with I > 2σ(I).
Crystal data for 8a. C15H12N2O3, M = 268.27, monoclinic,
P21, a = 8.5077(4), b = 9.6154(5), c = 9.3240(4) Å, β = 116.932(7)°,
Pharmacology
V = 680.02(6) Å3, Z = 2, d = 1.31 g cm−3, μ = 0.093 mm−1
.
Applying the agar plate diffusion technique,20 the compounds
were screened in vitro for their bactericidal activity against Gram
positive bacteria (Staphylococcus aureus) and Gram negative
bacteria (Escherichia coli and Pseudomonas aeroginosa), and
for their fungicidal activity against Fusarium oxysporium, Asper-
gillus niger and Candida albicans. In this method, a standard
5 mm diameter sterilized filter paper disc impregnated with the
compound (0.3 mg per 0.1 ml of DMF) was placed on an agar
plate seeded with the test organism. The plates were incubated
for 24 h at 37 °C for bacteria and 28 °C for fungi. The zone of
inhibition of bacterial and fungal growth around the disc was
observed.
A final refinement on F2 with 1659 unique intensities and
183 parameters converged at wR(F2) = 0.0784 (R(F) = 0.0346)
for 1509 observed reflections with I > 2σ(I).
ˉ
Crystal data for 8b. C15H11ClN2O3, M = 302.71, triclinic, P1,
a = 6.545(1), b = 10.072(2), c = 11.676(2) Å, α = 107.83(5), β =
101.23(4), γ = 92.80(3)°, V = 713.8(4) Å3, Z = 2, d = 1.41 g
cm−3, μ = 0.279 mm−1. A final refinement on F2 with 3257
unique intensities and 192 parameters converged at wR(F2) =
0.0972 (R(F) = 0.047) for 2050 observed reflections with
I > 2σ(I).
Compounds were tested against human liver (HEPG2), human
breast (MCF7), and cervix (HELA) carcinoma cell lines. The
method applied is similar to that reported by Skehan et al.41
using 20 Sulfo-Rhodamine-B stain (SRB). Cells were plated in a
96-multiwell plate (104 cells per well) for 24 h before treatment
with the test compound to allow attachment of the cell to the
wall of the plate. Different concentrations of the compound
under test (0, 1.0, 2.5, 5.0, and 10 μg ml−1) were added to the
cell monolayer in triplicate wells individual dose, and monolayer
cells were incubated with the compounds for 48 h at 37 °C and
in an atmosphere of 5% CO2. After 48 h, cells were fixed,
washed and stained with SRB stain, excess stain was washed
with acetic acid and attached stain was recovered with
Tris-EDTA buffer. Color intensity was measured in an ELISA
reader, and the relation between the surviving fraction and drug
concentration is plotted to get the survival curve of each tumor
cell line after the specified compound and the IC50 was
calculated.
Computational methods
DFT calculations were carried out using the B3LYP26 exchange–
correlation functionals, together with the standard 6-31G* basis
set.27 All stationary points were further optimised using the
6-311G* and 6-311+G* basis sets. The corresponding results are
given in the ESI† part. The optimisations were carried out using
the Berny analytical gradient optimisation method.28 The station-
ary points were characterized by frequency calculations in order
to verify that TSs have one and only one imaginary frequency.
The IRC29 paths were traced in order to check the energy
profiles connecting each TS to the two associated minima of the
proposed mechanism using the second order González–Schlegel
integration method.30 Solvent effects were considered at the
same level of theory by single-point energy calculations of the
gas-phase structures using
a self-consistent reaction field
(SCRF)31 based on the polarizable continuum model (PCM) of
the Tomasi’s group.32 Since this cycloaddition was carried out in
toluene, we selected its dielectric constant at 298.0 K, ε = 2.38.
Values of enthalpies, entropies and free energies in toluene were
calculated with standard statistical thermodynamics at 110 °C
and 1 atm.27 The electronic structures of stationary points were
analyzed by the natural bond orbital (NBO) method33 and by the
topological analysis of the ELF, η(r).34 The ELF study was per-
formed with the TopMod program35 using the corresponding
monodeterminantal wavefunctions of the selected structures of
Acknowledgements
The authors thank Rennes Métropole and the Institut
Universitaire de France for financial support to F.M. We are also
grateful to the Spanish Government (project CTQ2009-11027/
BQU).
This journal is © The Royal Society of Chemistry 2012
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Crystallogr., 1999, 32, 115.
23 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2007,
A64, 112.
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8444 | Org. Biomol. Chem., 2012, 10, 8434–8444
This journal is © The Royal Society of Chemistry 2012