Synthesis and thermal reactivity of 3-benzyl-7-trifluoromethyl-1H,3H- pyrrolo[1,2-c]thiazole-2,2-dioxide

Article abstract of DOI:10.1016/j.tet.2013.03.017

The generation and reactivity of 1-benzyl-5-trifluoromethyl-azafulvenium methide are described. Under microwave induced pyrolysis this intermediate could be trapped by dipolarophiles acting as a 4π as well as 8π dipole. It was observed that with dimethyl acetylenedicarboxylate the 1,3-dipolar cycloadduct was the major product whereas with N-substituted maleimides the major product results from the addition across the 1,7-position. FMO analysis of the cycloadditions corroborated the rationalization of the observed reactivity. Quantum chemical calculations carried out at the DFT level of theory allowed the rationalization of the stereoselectivity observed in the cycloaddition of 1-benzyl-5-trifluoromethyl-azafulvenium methide with N-substituted maleimides. The study revealed that exo-cycloaddition is the main reaction path for the 1,7-cycloaddition, while the endo-approach is the main mode of reaction leading to 1,3-cycloadducts. In addition, under flash vacuum pyrolysis or conventional thermolysis, 1-benzyl-5-trifluoromethyl-azafulvenium methide undergoes an allowed suprafacial sigmatropic [1,8]H shift leading to the efficient formation of 2-methyl-1-styryl-3-trifluoromethyl-1H-pyrrole.

Full text of DOI:10.1016/j.tet.2013.03.017

Tetrahedron 69 (2013) 3646e3655
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Synthesis and thermal reactivity of 3-benzyl-7-trifluoromethyl-
1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide
*
ꢀ
ꢀ
Walter Jose Pelaez, Teresa M.V.D. Pinho e Melo
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The generation and reactivity of 1-benzyl-5-trifluoromethyl-azafulvenium methide are described. Under
Received 21 January 2013
Received in revised form 28 February 2013
Accepted 5 March 2013
microwave induced pyrolysis this intermediate could be trapped by dipolarophiles acting as a 4
p as well
as 8 dipole. It was observed that with dimethyl acetylenedicarboxylate the 1,3-dipolar cycloadduct was
p
the major product whereas with N-substituted maleimides the major product results from the addition
across the 1,7-position. FMO analysis of the cycloadditions corroborated the rationalization of the
observed reactivity. Quantum chemical calculations carried out at the DFT level of theory allowed the
rationalization of the stereoselectivity observed in the cycloaddition of 1-benzyl-5-trifluoromethyl-
azafulvenium methide with N-substituted maleimides. The study revealed that exo-cycloaddition is the
main reaction path for the 1,7-cycloaddition, while the endo-approach is the main mode of reaction
leading to 1,3-cycloadducts. In addition, under flash vacuum pyrolysis or conventional thermolysis,
1-benzyl-5-trifluoromethyl-azafulvenium methide undergoes an allowed suprafacial sigmatropic [1,8]H
shift leading to the efficient formation of 2-methyl-1-styryl-3-trifluoromethyl-1H-pyrrole.
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 13 March 2013
Keywords:
Cycloadditions
Sigmatropic shifts
Dipoles
Azafulvenium methides
Trifluoromethylpyrroles
Flash vacuum pyrolysis
Microwave chemistry
DFT calculations
1. Introduction
reactions as 1,3-dipoles and/or 1,7-dipoles, leading to new
trifluoromethylpyrrole-annulated systems.4h
Fluorinated compounds play an important role in medicinal
chemistry since fluorine substitution in organic molecules often
leads to improved metabolic stability, bioavailability, and pro-
teineligand interactions.1 The influence of the CF3 group on phys-
iological activity is usually concerned with the increasing
lipophilicity, leading to the improvement of in vivo transport
characteristics. The high electronegativity of the CF3 group results
in quite a different electron density distribution and significantly
changes the reactivity of the molecules. There are only a few
examples of trifluoromethyl-containing pyrroles,2 however, some
of these compounds have demonstrated important insecticidal
action and mitochondrial uncoupling activity.3
Azafulvenium methide 3a, generated from 1H,3H-pyrrolo[1,2-c]
thiazole-2,2-dioxide 4 by thermal extrusion of sulfur dioxide,
showed site selectivity in the reaction with strong electron-
deficient dipolarophiles such as dimethyl acetylenedicarboxylate
(DMAD) and N-phenylmaleimide (NPM) leading exclusively to 1,3-
cycloadducts 5 and 6, respectively. However, in the cycloaddition of
dipole 3a with ethyl 3-phenylpropiolate, 1,7-cycloadduct 8 was also
formed. Frontier molecular orbital (FMO) analysis of the cycload-
ditions was in agreement with the observed selectivity.4h
Azafulvenium methides also participate in other pericyclic
reactions namely, sigmatropic [1,8]H shifts and 1,7-electro-
cyclizations giving vinylpyrroles.4,6 In fact, we demonstrated that
trifluoromethyl-azafulvenium methide 3b is converted efficiently
into C-vinylpyrrole 11 under thermolysis via 1,7-electrocyclization
followed by a rearrangement. The generation of dipole 3b in the
presence of N-phenylmaleimide gives the corresponding 1,3-
cycloadduct 12, although the formation of C-vinylpyrrole 11 as
a competitive reaction is also observed (Scheme 3).4h
We have previously demonstrated that 4,5-methoxycarbonyl-
azafulvenium methides 1 and 4,5-methoxycarbonyl-diazafulvenium
methides 2 are versatile building blocks for the synthesis of func-
tionalized pyrroles and pyrazoles (Scheme 1).4,5 These extended
dipolar systems can, in principle, act as 4p 1,3-dipoles or as 8p
1,7-dipoles, although the typical reactivity is that expected for
1,7-dipoles. However, we have shown that 5-trifluoromethyl-aza-
fulvenium methide derivatives 3 have a different reactivity pattern.
In fact, these reactive intermediates participate in cycloaddition
Herein, the chemistry of a new 5-trifluoromethyl-azafulve-
nium methide derivative was studied in order to better un-
derstand the chemistry of azafulvenium methides, in particular to
know the structural features that allow these intermediates to
participate in reactions with dipolarophiles as 1,3-dipoles and
1,7-dipoles. It was also our aim to evaluate the scope of this
* Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.017

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3647
CO2Me
CO2Me
CO2Me
[8π+2π]
a
b
Cycloaddition
CO2Me
N
N
a
b
X
X
R
R
1 X = CR Azafulvenium methide
2 X = N Diazafulvenium methide
F3C
5
[8π+2π]
Cycloaddition
1,3-Dipolar
Cycloaddition
4
6
3
7
a
b
a
b
2
N
1
F3C
R1
3
F3C
5-Trifluoromethyl-
azafulvenium methides
a
b
N
R1
N
a
b
F3C
Me
R1
a
N
Scheme 3. Pericyclic reactions of azafulvenium methide 3b.4h
b
R1
methide, was prepared following a known general methodology
(Scheme 4).4h,6 The reaction of thiazolidine 13 with 4-ethyloxy-1,1,1-
trifluorobut-3-ene-2-one (14) was diastereoselective, giving the
expected 1-butenyl-thiazolidine 15 in 84% yield. Two rotamers were
observed in the 1H NMR and 13C NMR spectra of this heterocycle
recorded at ambient temperature as previously observed for other
1-butenyl-thiazolidine derivatives.4h Cyclization of thiazolidine 15
in the presence of trifluoroacetic anhydride gave 7-trifluoromethyl-
1H,3H-pyrrolo[1,2-c]thiazole 16 in good yield as single enantiomer
Scheme 1. Cycloaddition of aza- and diazafulvenium methides.
F3C
N
O2S
F3C
4
([
with the structure of (R)-3-phenyl-7-trifluoromethyl-1H,3H-pyr-
rolo[1,2-c]thiazole ([
a]
D þ91.3). The stereochemistry of 16 was assigned by comparison
CO2Me
CO2Me
MW, 10 min
240-245°C
1,2,4-TCB
N
a
]
þ159), prepared by a similar synthetic
Me
D
- SO2
methodology, whose absolute configuration was determined by X-
ray crystallography.4h Catalytic oxidation of thiazolidine 16 afforded
sulfone 17 in good yield, isolated as a racemic mixture.
DMAD
61%
5
F3C
Me
F3C
O
H
H
1,3-DC
NPM
72%
N
N Ph
N
3a
O
6
Ph
CO2Et
F3C
CF3
Ph
Ph
+
N
Me
N
EtO2C
CO2Et
72% (82:18)
8
7
Scheme 2. Cycloaddition of azafulvenium methide 3a with electron-deficient
dipolarophiles.4h
synthetic approach to functionalized trifluoromethylpyrroles,
including trifluoromethylpyrrole-annulated derivatives.
Scheme 4. Synthesis of 7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide 17.
2. Results and discussion
2.2. Generation and reactivity of 1-benzyl-5-(trifluoromethyl)
2.1. Synthesis of 7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thia-
azafulvenium methide
zole-2,2-dioxide
7-Trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide 17
was subjected to flash vacuum pyrolysis (FVP), microwave induced
7-Trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide 17,
the precursor of the new 1-benzyl-5-trifluoromethyl-azafulvenium

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3648
pyrolysis (MWIP), and conventional heating to carry out the
extrusion of sulfur dioxide leading to the target azafulvenium
methide 18 (Scheme 5).
F3C
F3C
7
7
8
8
H
H
8b
6
8a
6
8a
O
1
O
1
8b
Me
Me
N
N
3a
3a
10
4
N
N
3
H
4 H
R
R
3
Ph
Ph
H H
10
FVP
450 °C
MWIP
240 °C
1,2,4-TCB
Reflux
F3C
F3C
O
O
F3C
O2S
22Cis
22Trans
N
N
a R = CH3
b R = Ph
D
H4-C4-C3a-H3a= 17.9°
a R = CH3
b R = Ph
D
H4-C4-C3a-H3a= 121.2°
N
D
H4-C4-C3a-H3a= 17.4°
D
H4-C4-C3a-H3a= 121.2°
Ph
Ph
Ph
Fig. 1. Estimated dihedral angles for 3a,4-dihydropyrrolo[3,4-a]pyrrolizine-
1,3(2H,8bH)-diones 22.
18a
18b
17
Scheme 5. Generation of azafulvenium methide 18 by FVP, MWIP, and conventional
heating.
to establish that the azafulvenium 18 reacts with N-phenyl- and
N-methylmaleimide affording only the trans-stereoisomer.
Furthermore, the 1H NMR spectrum of a cis/trans mixture of
a similar compound, bearing a methyle instead of the benzyle
group, shows the major cycloadduct with the same coupling
pattern and a minor cycloadduct, which was assigned as being
the cis-isomer since the coupling between H4 and H3a could be
observed.
The structural assignment of compounds 23 was supported by
NOESY spectra. Relative high-intensity cross-peaks between H4
and H9b and connectivity between the methylene group (at C10)
and H3a were found, which is in agreement with the estimated
distances between hydrogen atoms (Fig. 2), establishing that
compounds 23 have trans configuration.
FVP or conventional thermolysis of 17 in the absence of dipo-
larophiles led to the efficient formation of N-styrylpyrrole 19 via an
allowed suprafacial sigmatropic [1,8]-H shift in the 8
system of the in situ generated azafulvenium methide 18
(Scheme 5). Although azafulvenium methide 18 exists in equilib-
rium of at least two conformers, only conformer 18a bears a hy-
drogen in the appropriate position to undergo the pericyclic
reaction (see below, theoretical calculations).
Under MWIP, azafulvenium methide 18 was also generated and
trapped in cycloaddition reactions (Scheme 6). The reaction with
DMAD gave a mixture of 1,3- and 1,7-cycloadducts 20 and 21 in 89:11
ratio, respectively. Under the same microwave induced reaction
conditions, dipole 18 reacted with N-phenylmaleimide (NPM) and
N-methylmaleimide (NMM) also giving 1,3- and 1,7-cycloadducts.
However, the major products resulted from the addition across the
1,7-position, theselectivityoppositetothe oneobservedwith DMAD.
It is important to note that cycloadducts 22 and 23 were obtained in
a diastereoselective manner. Attempts to carry out the cycloaddition
of azafulvenium methide 18 with ethyl 3-phenylpropiolate, only led
to the formation of 2-methyl-1-styryl-3-trifluoromethyl-1H-pyrrole
19, which was isolated in high yield (90%).
p 1,7-dipolar
2.3. Theoretical study
Quantum chemical calculations, carried out at the DFT level
of theory (B3LYP functional), have been carried out in order to
investigate the structure and preferred conformers of 5-
trifluoromethyl-azafulvenium methides 3a and 18 in the gas
phase (Fig. 3, Table S1). Full geometry optimizations were per-
F3C
F3C
Me
DMAD
CO2Me
+
N
N
N
MW, 240 °C
Ph
F3C
H
F3C
MeO2C
F3C
Me
10 min, 1,2,4-TCB
Ph
CO2Me
44% (89:11)
F3C
FVP
90%
MeO2C
N
N
20
21
N
O
1,2,4-TCB
reflux
NR
F3C
Ph
Ph
19
85%
Ph
O
H
O
18a
18b
N
Me
Ph
+
H
Ph
MW, 240 °C
10 min, 1,2,4-TCB
O
N
R
H
H
H
H
N
O
R
O
88% (28:72)
77% (24:76)
22a R = CH3
22b R = Ph
23a R = CH3
23b R = Ph
Scheme 6. Reactivity of 5-trifluoromethyl-azafulvenium methide 18.
The structural assignment of cycloadducts 20e23 was based on
one-dimensional NMR spectra (1H, 13C, 19F) and two-dimensional
HMQC, HMBC, and NOESY spectra.
In particular, structures of compounds 22 were established
mainly on the basis of the 1H NMR spectra and the estimated
dihedral angle between H4 and H3a (Fig. 1). In fact, scalar cou-
pling between these protons could not be detected, allowing us
formed, followed by harmonic frequency calculations, at the same
level of theory, which also allowed characterization of the nature of
the stationary points. The azafulvenium methide 3a was found to
be planar. On the other hand, the results show that 5-
trifluoromethyl-azafulvenium methide 18 can exist in two differ-
ent conformers, conformer 18b slightly more stable than conformer
18a having the inward benzyl group (15.8 kJ molꢀ1).

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3649
dipole have the highest orbital coefficients, indicating that the 1,3-
cycloaddition should be favored over the 1,7-cycloaddition (Fig. 5).
This is in agreement with the selectivity observed experimentally
in the cycloaddition of 18 with DMAD. However, with N-substituted
maleimides, the 1,7-cycloadducts became the major products, and
no cycloaddition was observed with ethyl 3-phenylpropiolate.
Thus, in the case of azafulvenium methide 18, bearing an additional
benzyl group at C1, the selectivity can only be explained consid-
ering a combination of electronic and steric factors.
9b
9c
H
H
CF3
O
1
H
8
8a
a R = CH3
b R = Ph
r
H4-H9b = 2.96 Å
9
9a
7
r
H10-H3a= 2.49 Å
R N
N
H
Ph
3
6
r
H4-H9b = 2.97 Å
H
4
O
3a
10
r
H10-H3a = 2.47Å
23Trans
Fig. 2. Estimated distances between hydrogen atoms for 3a,4,9,9a-tetrahydro-1H-
pyrrolo[3,4-f]indolizine-1,3(2H)-diones 23.
In order to be able to rationalize the stereoselective synthesis of
trans-cycloadducts (22 and 23) from the cycloaddition of aza-
Fig. 3. Optimized geometries of 5-trifluoromethyl-azafulvenium methide (3a) and of the two relevant conformers of 1-benzyl-5-trifluoromethyl-azafulvenium methide (18), at
B3LyP(6-31þG(d,p)) level of theory.
We have previously reported that the frontier molecular
orbital (FMO) analysis of the cycloaddition reactions of tri-
fluoromethyl-azafulvenium methide 3a indicated that the HOMO-
dipoleeLUMOdipolarophile is the dominant interaction for strong
electron-deficient dipolarophiles such as DMAD and NPM. In the
HOMO dipole controlled reaction, the C1 and C3 reactive sites of
dipole 3a have the highest orbital coefficients indicating that
the 1,3-cycloaddition should take place exclusively as observed
experimentally. For the less-activated dipolarophiles such as ethyl
3-phenylpropiolate, the LUMOdipoleeHOMOdipolarophile interaction
must also be considered. The LUMO of the azafulvenium methide
3a is characterized by having the C1 and C7 reactive sites with the
highest orbital coefficients, favoring the 1,7-cycloaddition. This
rationalization explains the formation of both 1,3-cycloadduct and
1,7-cycloadduct in the reaction of azafulvenium methide 3a with
ethyl 3-phenylpropiolate (Scheme 2).4h
FMO analysis of the cycloaddition reactions of 18a and 18b,
summarized in Fig. 4 and Table 1, has been carried out. The values of
the HOMO and LUMO energies of azafulvenium methide 3a are
lower than the corresponding values obtained for azafulvenium
methide 18. Nevertheless, HOMOdipoleeLUMOdipolarophile is still the
dominant interaction for strong electron-deficient dipolarophiles.
Analyzing the HOMOdipole controlled cycloaddition of azafulvenium
methide 18, we found that the C1 and C3 reactive sites of the
fulvenium methide 18 with N-substituted maleimides, quantum
chemical calculations were carried out at the DFT level of theory
(see Supplementary data). The B3LYP functional, selected for
this task, has been shown to be an effective method for modeling
dipolar cycloadditions.7 In this theoretical study transition
states resulting from the following reactions were considered:
(i) exo-1,7-cycloaddition; (ii) endo-1,7-cycloaddition; (iii) exo-1,3-
cycloaddition and (iv) endo-1,3-cycloaddition. The activation en-
ergies corresponding to these transitions states are reported in
Table 2. The optimized geometries of relevant transition structures
for the cycloaddition of azafulvenium 18b and maleimides are
presented in Fig. 6.
Calculations carried out to estimate the relative stability of
the cis- and trans-1,7(1,3)-cycloadducts revealed that the cis-
derivatives, which were not detected, are around 17 kJ molꢀ1 less
stable. On the other hand, calculations also indicate that trans-1,7-
cycloadducts 23, identified as the major products, are around
8 kJ molꢀ1 more stable than the trans-1,3-counterparts 22.
In this analysis of the cycloaddition of azafulvenium methide 18
with maleimides, the two conformers 18a and 18b were consid-
ered. The synthesis of the trans-1,7-cycloadducts 23 could only
result from the endo-1,7-cycloaddition of conformer 18a through
transition state TSendo1,7[18a] or from the exo-1,7-cycloaddition of
conformer 18b through transition state TSexo1,7[18b] (Scheme 7).

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3650
F3C
F3C
F3C
N
N
OCH2CH3
CH3
N
OCH3
Ph
N
C
N
O
C
O
O
O
O
Ph
18a
Ph
O
Ph
O
18b
C
OCH3
3a
H
H
H
H
LUMO
HOMO
(eV)
Fig. 4. Relative energies (eV) for dipoles 3a and 18 and different dipolarophiles [B3LyP/6-31þG(d,p)].
Table 1
Frontier orbital energies (eV) for 3a and 18 and different dipolarophiles at AM1, PM3, HF/6-31G(d), and B3LyP/6-31þG(d,p) theoretical level
HOMO
AM1
LUMO
AM1
PM3
HF/6-31G(d)
B3LyP/6-31þG(d,p)
PM3
HF/6-31G(d)
B3LyP/6-31þG(d,p)
3a
18a
18b
NPM
ꢀ7.83
ꢀ7.64
ꢀ8.19
ꢀ6.15
ꢀ6.08
ꢀ5.00
ꢀ4.82
ꢀ4.86
ꢀ6.87
ꢀ7.81
ꢀ8.40
ꢀ7.09
ꢀ1.24
ꢀ1.19
ꢀ1.18
ꢀ1.25
ꢀ1.14
ꢀ0.51
ꢀ0.67
ꢀ1.44
ꢀ1.43
ꢀ1.42
ꢀ1.22
ꢀ1.23
ꢀ0.36
ꢀ0.66
1.40
1.65
1.59
1.51
1.55
3.01
2.25
ꢀ2.81
ꢀ2.56
ꢀ2.60
ꢀ3.10
ꢀ3.03
ꢀ3.30
ꢀ2.20
ꢀ8.02
ꢀ8.07
ꢀ7.67
ꢀ6.12
ꢀ11.61
ꢀ10.51
ꢀ11.96
ꢀ9.68
ꢀ11.49
ꢀ10.18
ꢀ11.83
ꢀ9.72
ꢀ11.52
ꢀ11.06
ꢀ11.72
ꢀ8.94
NMM
DMAD
Ethyl 3-phenyl-propiolate
Fig. 5. Surface of electron density, isosurface of HOMO and LUMO of 18a,b and calculated MO coefficients (PM3) at the reactive sites C1, C3, and C7 are also presented.

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3651
Table 2
barrier, relative to the conformer 18b for this 1,3-cycloaddition. In
addition, NBO calculation on the transition states TSendo1,7[18a]
and TSexo1,7[18b], also showed the same kind of effective energy
interactions between the N5eC26 two-center bond (BD), the C1eC37
two-center bond (BD), as well as the N5eC26 two-center anti-
Transition state energies at B3LyP/6-31þG(d,p) theoretical level, calculated relative
to conformer 18b and the corresponding maleimide
1,7-Cycloaddition
B3LyP/6-31þ
1,3-Cycloaddition
B3LyP/6-31þ
G(d,p) kJ molꢀ1
G(d,p) kJ molꢀ1
TSexo1,7[18b]Me
TSendo1,7[18a]Ph
TSendo1,7[18a]Me
TSexo1,7[18b]Ph
5.14
24.78
25.84
3.49
TSexo1,3[18a]Me
TSendo1,3[18b]Ph
TSendo1,3[18b]Me
TSexo1,3[18a]Ph
19.40
12.40
8.93
bonding (BD
*
), all with the
p
antibonding orbital (
p ) of C40eC42
*
favoring the formation of TSendo1,7[18a] by about 9 kJ molꢀ1 (Fig. 5).
Nevertheless, this effective stabilization in the endo-cycloaddition
18.00
Fig. 6. Geometries of transition states for the cycloaddition of azafulvenium methide 18b with NPM, TSendo1,3 (a) and TSexo1,3 (b), and with NMM, TSendo1,7 (c) and TSexo1,7 (d),
calculated at B3LyP(6-31þG(d,p)) level of theory.
Calculations showed that the lower energy channel to obtain the
main product is through TSexo1,7[18b], about 20 kJ molꢀ1 lower
in energy than TSendo1,7[18a] (Fig. 7, Table 2). This result allowed
us to conclude that compounds 23 are obtained via exo-1,7-
cycloaddition of conformer 18b.
was not large enough to compensate the large energy barrier
through this reaction path, which means that the steric factors play
an important role in this cycloaddition (Fig. 6).
3. Conclusion
The possible mechanism pathways regarding the cycloadditions
of azafulvenium methides 18 with maleimides leading to trans-1,3-
cycloadducts are shown in Scheme 8. The trans-1,3-cycloadducts 22
could be produced only via endo-cycloaddition of conformer 18b
through transition state TSendo1,3[18b] or as the result of the exo-
cycloaddition of conformer 18a through transition state TSexo1,3
[18a].
The results of the quantum chemical calculations demonstrate
that the stereoselective synthesis of heterocycles 22 is achieved via
endo-1,3-cycloaddition through transition state TSendo1,3[18b]
(Fig. 7, Table 2).
The generation and reactivity of 1-benzyl-5-trifluoromethyl-
azafulvenium methide were described. This reactive intermediate
undergoes sigmatropic [1,8]H shift to give the corresponding N-
styrylpyrrole and participates in cycloaddition reactions with
DMAD and N-substituted maleimides to afford trifluoromethyl-
pyrrole-annulated derivatives resulting from the addition across
the 1,3- and 1,7-positions.
The higher selectivity of 5-trifluoromethyl-azafulvenium
methide for the formation of 1,3-cycloadducts when compared with
1-benzyl-5-trifluoromethyl-azafulvenium methide, bearing an ad-
ditional benzyl group at C1, indicates that a combination of electronic
and steric factors determines the outcome of the cycloaddition. FMO
analysis of the cycloadditions corroborated this observation.
Quantum chemical calculations were carried out at the DFT level
of theory in order to be able to rationalize the stereoselective
synthesis of trans-1,3-cycloadducts and trans-1,7-cycloadducts
Calculations on specific NBO donoreacceptor interactions in the
transition states TSendo1,3[18b] and TSexo1,3[18a], showed that
there were effective energy interactions between the N5eC26 two-
center bond (BD), the C4 lone pair of electrons (LP) as well as the
N5eC26 two-center antibonding (BD
orbital ( ) of C36eC38 favoring the formation of TSendo1,3[18b] by
about 13 kJ molꢀ1 according to the results obtained on the energy
*
), all with the p antibonding
p
*
from
the
cycloaddition
of
1-benzyl-5-trifluoromethyl-

ꢀ
W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3652
CF3
O
CF3
CF3
O
H
R
O
H
H
N
Cycloaddition
Ph
Cycloaddition
R
R
N
N
R
N
O
N
endo
exo
N
H
4
3a
H
H
H
O
H
O
H
Ph
Ph
TSendo1,7[18b]
TSexo1,7[18a]
cis-1,7-cycloadducts
CF3
O
H
O
R
CF3
CF3
O
H
N
N
R= CH3 Ph
TS 25.8 24.9
R
N
H
R= CH3 Ph
4
H
N
3a
O
H
N
TS 5.1
3.5
N
H
H
O
O
H
H
Ph
Ph
TSexo1,7[18b]
Ph
TSendo1,7[18a]
23a R = CH3
23b R = Ph
trans-1,7-cycloadducts
Scheme 7. 1,7-Cycloaddition of azafulvenium methide 18 with NMM and NPM.
azafulvenium methide with N-substituted maleimides. The study
revealed that exo-cycloaddition is the main reaction path for the
1,7-cycloaddition, while the endo-approach is the main mode of
reaction leading to 1,3-cycloadducts.
4. Experimental section
4.1. General
Microwave reactions were carried out in a microwave reac-
tor CEM Focused Synthesis System Discover S-Class using 10 mL
microwave tubes. The reaction temperatures were measured by
infrared surface detector during microwave heating. Thiazolidine
13,8 1-butenyl-thiazolidine 15, 1H,3H-pyrrolo[1,2-c]thiazole 16,
and 7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide 17
were prepared by modifying
a procedure described in the
literature.5
19F NMR spectra were recorded on an instrument operating at
376 MHz. 1H NMR spectra were recorded on an instrument oper-
ating at 400 MHz. 13C NMR spectra were recorded on an instrument
Fig. 7. B3LyP(6-31þG(d,p)) energy (kJ molꢀ1) calculated relative to conformer 18b
and NMM.
F3C
Me
F3C
O
F3C
R
H
O
H
N
N
N
H
R= CH3 Ph
TS 8.9 12.4
R= CH3 Ph
TS 19.4 18.0
H
4
H
O
N
N
H
O
N
R
H
3a
H H
R
R
H
Ph
Ph
O
H
H
22a R = CH3
22b R = Ph
Ph
O
H
TSendo1,3[18b]
TSexo1,3[18a]
trans-1,3-cycloadducts
F3C
F3C
O
R
F3C
H
H
N
H
O
N
H
H
H
Me
N
Cycloaddition
Cycloaddition
H
O
H
O
N
N
endo
exo
H 4
N
Ph
R
H
3a
H
H
Ph
Ph
O
O
H
TSexo1,3[18b]
TSendo1,3[18a]
cis-1,3-cycloadducts
Scheme 8. 1,3-Cycloaddition of azafulvenium methide 18 with NMM and NPM.

ꢀ
W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3653
operating at 100 MHz. Chemical shifts are expressed in parts per
million (ppm) relative to internal tetramethylsilane (TMS), and
coupling constants (J) are in hertz (Hz). Infrared (IR) spectra were
recorded on a Fourier transform spectrometer (FTIR). Mass spectra
were recorded under electron impact (EI) or electrospray ionization
(ESI). High-resolution mass spectra (HRMS) were obtained on an
electron impact (EI) or electrospray (ESI) TOF mass spectrometer.
Melting points were determined in open glass capillaries and are
uncorrected. Thin-layer chromatography (TLC) analyses were per-
formed using precoated silica gel plates. Flash column chroma-
tography was performed with silica gel 60 as the stationary phase.
192(100%), 148(33%), 135(5%), 104(7%), 91(12%). HRMS (EI-TOF):
calculated C14H12F3NS [Mþ]: 383.0643. Found: 383.0647.
4.4. 3-Benzyl-7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thia-
zole-2,2-dioxide (17)
A
solution of (R)-3-benzyl-7-trifluoromethyl-1H,3H-pyrrolo
[1,2-c]thiazole 16 (0.567 g, 2 mmol) in ethyl acetate (3 mL) was
charged with Na2WO4$2H2O (1 M solution in water, 45 L),
C6H5PO3H2 (1 M solution in water, 45 L), CH3N[(CH2)7CH3]3Cl (1 M
solution in methanol, 45 L), and aqueous 35% H2O2 (75 mmol).
m
m
m
This mixture was vigorously stirred at 40 ꢁC. After 3 days, a new
load of catalysts and H2O2 was added and stirred again for three
more days at 40 ꢁC. The reaction mixture was washed with 10%
(w/v) aqueous sodium bisulfite and the aqueous phase was
extracted with ethyl acetate. The organic phase was then dried over
anhydrous Na2SO4 and the solvent evaporated off giving a pale
yellow oil which was purified by column chromatography [hexane,
hexane/ethyl acetate (9:1), hexane/ethyl acetate (8:2)] to give
sulfone 17 as a white solid (0.448 g, 71%).
4.2. (2R,4R)-2-Benzyl-3-[(E)-4,4,4-trifluoro-3-oxobut-1-enyl]
thiazolidine-4-carboxylic acid (15)
A solution of 4-ethyloxy-1,1,1-trifluoro-3-buten-2-one (3.24 g,
19.3 mmol) in acetonitrile (10 mL) was added dropwise to a solution
of thiazolidine-4-carboxylic acid 13 (4.73 g, 21.2mmol) in acetonitrile
(90 mL) at room temperature. After stirring for 10 min, the solution
was heated at 60 ꢁC for 24 h. Then the reaction mixture was filtered
and the solvent was removed in vacuum. Diethyl ether (120 mL) and
water (120 mL) were added and the two layers separated. The
aqueous phase was extracted with diethyl ether (2ꢂ120 mL) and
the combined organic phases were dried (MgSO4) and the solvent
removed in vacuum. The resulting pale yellow oil was purified by
column chromatography [hexane, hexane/ethyl acetate (7:3), then
hexane/ethyl acetate (1:1)] to give 15 as a solid (5.60 g, 84%).
26
4.4.1. Data for 17. Mp 110e111 ꢁC (amorphous solid). [
a
]
0.0
D
(c, 1.0 CHCl3). 19F (376 MHz, CDCl3):
CDCl3):
d
ꢀ56.13. 1H NMR (400 MHz,
d
3.15 (dd, J1¼14.6 Hz, J2¼4.8 Hz, 1H), 3.59 (dd, J1¼14.6 Hz,
J1¼8.0 Hz, 1H), 4.04 (d, J¼15.5, 1H), 4.37 (d, J¼15.5 Hz, 1H), 5.16 (dd,
J1¼8.0 Hz, J2¼4.8 Hz, 1H), 6.34 (d, J¼2.8 Hz, 1H), 6.41 (d, J¼2.8 Hz,
1H), 7.15 (m, 2H), 7.34 (m, 3H). 13C NMR (100 MHz, CDCl3):
d 132.7,
129.8, 129.2, 128.3, 123.2 (q, JCF ¼266.3 Hz), 121.4 (q, JCCeCF ¼3.9),
3
3
119.1, 111.8 (q, JCeCF ¼37.4 Hz), 75.5, 49.8, 37.3, 135.3, 134.6
4.2.1. Data for 15. Mp 184e185 ꢁC (amorphous solid, from hexane/
3
(q, J
¼3.8 Hz), 129.8, 128.6, 127.6, 124.0 (q, J ¼265.6 Hz),
ethyl acetate). 19F NMR (376 MHz, DMSO-d6):
d
ꢀ74.99. 1H NMR
CCeCF3
CF3
115.1,111.3,106.2 (q, JCeCF ¼36.7 Hz), 65.0, 44.8, 27.8. IR (KBr, cmꢀ1):
3
(400 MHz, DMSO-d6): two conformers. Major:
d
8.15 (d, J¼12.7 Hz,
3169, 3093, 3037, 2981, 2963, 2950, 1600, 1484, 1457, 1438, 1400,
1330, 1262, 1175, 1133, 973, 749, 719, 697. MS (EI): 315(Mþ, 3%),
251(89%), 250(80%), 236(33%), 232(9%), 182(9%), 174(4%), 167(7%),
154(3%), 148(3%), 113(4%), 104(100%), 78(9%). HRMS (EI-TOF): cal-
culated C14H12F3NO2S [Mþ]: 315.0541. Found: 315.0542.
1H), 5.64 (d, J¼12.7 Hz,1H), 5.43 (m, 1H), 5.08 (d, J¼6.5 Hz,1H), 3.27
(m, 2H), 3.12 (m, 2H). Minor:
8.23 (d, J¼12.4 Hz, 1H), 5.35 (m, 1H),
5.32 (d, J¼12.4 Hz, 1H), 4.94 (d, J¼5.1 Hz, 1H), 3.27 (m, 2H), 3.01 (m,
2H). 13C NMR (100 MHz, DMSO-d6): two conformers. Major:
175.7
d
d
(q, JCOeCF ¼31.6), 171.0, 153.4, 136.5, 129.9, 128.3, 126.9, 117.5
3
(q, JCF ¼292.0), 90.5, 67.9, 65.5, 38.3, 30.8. Minor:
d 175.5 (q,
3
4.5. Synthesis of 2-methyl-1-styryl-3-trifluoromethyl-1H-
pyrrole (19)
JCOeCF ¼31.6), 169.0, 152.2, 136.6, 130.0, 128.2, 126.9, 117.4
3
(q, JCF ¼291.25), 90.1, 69.7, 63.8, 42.8, 31.4. IR (KBr, cmꢀ1):
3
3300e2700 br, 3031, 2933, 1724, 1659, 1558, 1456, 1383, 1283, 1265,
1137, 1100, 787, 699. HRMS (ESI-TOF): calculated C15H15F3NO3S
[MþþH]: 346.07072. Found: 346.07193.
Flash vacuum pyrolysis. Pyrolysis of the 3-benzyl-7-trifluoro-
methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2ꢀ-d5ioxide (17) (107.2 mg,
0.34 mmol) at 450e475 ꢁC and 1ꢂ10
to 2ꢂ10ꢀ5 mbar onto
a surface cooled at ꢀ196 ꢁC over a period of 1 h gave a colorless
pyrolysate [The rate of volatilization of the starting material was
controlled by the use of a pre-oven, which heated the sample at
70e80 ꢁC.]. The pyrolysate was allowed to warm to room temper-
ature and removed from the cold finger with dichloromethane. The
solvent was removed in vacuum and the pyrolysate was recrystal-
lized from a mixture of hexane/ethyl acetate to give 2-methyl-1-
styryl-3-trifluoromethyl-1H-pyrrole 19, in high yield as a white
solid (76.9 mg, 90%).
4.3. (R)-3-Benzyl-7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thia-
zole (16)
To a stirred solution of N-(unsaturated ketone) thiazolidine-4-
carboxylic 15 (5.87 g, 17.0 mmol) under nitrogen in dry dichloro-
methane (140 mL), trifluoroacetic anhydride (4.28 g, 20.4 mmol)
was added dropwise at 0 ꢁC. After stirring at 0 ꢁC for 1 h and at
room temperature for 7 h, the solvent was removed in vacuum. The
resulting brown oil was purified by flash chromatography [hexane,
hexane/ethyl acetate (9:1)] to give the corresponding (R)-3-benzyl-
7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole 16 as a white solid
(3.66 g, 76%).
Conventional heating. A suspension of 7-trifluoromethyl-1H,3H-
pyrrolo[1,2-c]thiazole-2,2-dioxide 17 (50.5 mg, 0.16 mmol) in 1,2,4-
trichlorobenzene (1 mL) was heated at reflux under dry nitrogen
for 6 h. After cooling to room temperature, the pyrolysate was
purified by column chromatography [hexane, hexane/ethyl acetate
(9:1)] to give 2-methyl-1-styryl-3-trifluoromethyl-1H-pyrrole 19,
which was isolated in high yield as a white solid (34.2 mg, 85%).
26
4.3.1. Data for 16. Mp 40e41 ꢁC (amorphous solid). [
a]
þ91.3 (c,
D
1.1 CHCl3). 19F (376 MHz, CDCl3):
CDCl3):
d
ꢀ55.58. 1H NMR (400 MHz,
d
3.26 (m, 1H), 3.74 (d, J¼13.7 Hz, 1H), 3.92 (d, J¼13.7 Hz,
1H), 5.60 (m, 1H), 6.41 (d, J¼2.5 Hz, 1H), 6.48 (d, J¼2.5 Hz, 1H), 7.10
4.5.1. Data for 1H-pyrrole 19. Mp 76e77 ꢁC (amorphous solid). 19F
(m, 2H), 7.29 (m, 3H). 13C NMR (100 MHz, CDCl3):
d
135.3, 134.6 (q,
(376 MHz, CDCl3):
d
ꢀ54.93.1H NMR (400 MHz, CDCl3):
d 2.41 (s, 3H),
JCCeCF ¼3.8 Hz), 129.8, 128.6, 127.6, 124.0 (q, JCF ¼265.6 Hz), 115.1,
6.38 (d, J¼2.8 Hz, 1H), 6.66 (d, J¼14.3 Hz, 1H), 6.96 (d, J¼2.8 Hz, 1H),
3
3
111.3,106.2 (q, JCeCF ¼36.7 Hz), 65.0, 44.8, 27.8. IR (KBr, cmꢀ1): 3112,
7.26 (d, J¼14.3 Hz, 1H), 7.36 (m, 5H). 13C NMR (100 MHz, CDCl3):
3
3031, 2922, 1587, 1485, 1454, 1437, 1393, 1374, 1258, 1224, 1171,
1103, 1030, 978, 751, 698. MS (EI): 283(Mþ, 5%), 250(10%), 236(3%),
d
135.1, 129.0, 128.0, 127.4, 126.3, 124.4(q, JCF ¼266.3 Hz), 123.5,
3
119.5, 116.9, 113.0 (q, JCeCF ¼35.4 Hz), 107.9 (q, JCCeCF ¼2.9 Hz), 10.5.
3
3

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3654
IR (KBr, cmꢀ1): 3115, 3085, 3028, 2981, 2929, 1655, 1587, 1495, 1440,
1268, 1098, 1019, 934, 750, 722, 688. MS (EI): 251(Mþ, 81%),
250(100%), 236(22%), 232(11%), 181(20%), 167(15%), 148(6%),
104(42%), 103(10%), 77(8%). HRMS (EI-TOF): calculated C14H12F3N
[Mþ]: 251.0922. Found: 251.0917.
4.6.3. 4-Benzyl-6-methyl-2-phenyl-7-trifluoromethyl-3a,4-dihy-
dropyrrolo[3,4-a]pyrrolizine-1,3(2H,8bH)-dione (22b) and 4-benzyl-
2-phenyl-8-trifluoromethyl-3a,4,9,9a-tetrahydro-1H-pyrrolo[3,4-f]
indolizine-1,3(2H)-dione (23b). Isolated as a 24:76 mixture (de-
termined by 1H NMR), 77% yield.
4.6. General procedure for cycloadditions under MWIP
conditions
4.6.3.1. Data for 22b. Mp 135e136 ꢁC (amorphous solid). 19F
(376 MHz, CDCl3):
d
ꢀ55.21. 1H NMR (400 MHz, CDCl3):
d 2.39
(s, 3H), 3.10 (dd, J1¼14.3 Hz, J2¼5.2 Hz, 1H), 3.18 (dd,
J1¼14.3 Hz, J2¼4.0 Hz, 1H), 3.52 (d, J¼7.49 Hz, 1H), 3.79 (d,
J¼7.49 Hz, 1H), 5.11 (m, 1H), 6.17 (s, 1H), 6.82 (d, J¼6.1 Hz, 2H),
7.17 (d, J¼7.37 Hz, 2H), 7.25 (d, J¼6.3 Hz, 2H), 7.40 (m, 4H). 13C
A
suspension of 7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thia-
zole-2,2-dioxide 17 (53.6 mg, 0.17 mmol) and dipolarophile
(1.2e4.0 equiv) in 1,2,4-trichlorobenzene (0.5 mL or 1 mL) was ir-
radiated in the microwave reactor at the temperature and for the
time indicated in each case. After cooling to room temperature, the
mixture was purified by flash chromatography [hexane] to remove
1,2,4-trichlorobenzene followed by elution with hexane/ethyl
acetate to obtain the corresponding cycloadducts.
NMR (100 MHz, CDCl3):
d 173.2, 176.2, 134.3, 131.4, 129.5, 129.3,
129.1, 129.0, 128.1, 127.9, 126.3, 124.3 (q, JCeCeCF ¼3.6 Hz), 124.0
3
(q, JCF ¼267.0 Hz), 116.5 (q, JCeCF ¼36.1 Hz), 100.6 (q,
3
3
JCeCeCF ¼2.9 Hz), 43.6, 53.3, 59.3, 41.0, 10.9. MS (EI): 424(Mþ,
3
13%), 333(12%), 187(7%), 186(100%), 173(2%), 166(7%), 117(8%),
91(8%). HRMS (EI-TOF): calculated C24H19F3N2O2 [Mþ]:
424.1398. Found: 424.1399.
4.6.1. Dimethyl 3-benzyl-5-methyl-6-trifluoromethyl-3H-pyrrolizine-
1,2-dicarboxylate (20) and dimethyl 5-benzyl-1-trifluoromethyl-5,8-
dihydroindolizine-6,7-dicarboxylate (21). Isolated as an 89:11 mix-
ture (determined by 1H NMR), 44% yield.
4.6.3.2. Data for 23b. Mp 94e95 ꢁC (amorphous solid). 19F
(376 MHz, CDCl3):
d
ꢀ54.42. 1H NMR (400 MHz, CDCl3):
d 3.00(dd,
J1¼15.5 Hz, J2¼6.8 Hz, 1H), 3.31(dd, J1¼9.2 Hz, J2¼3.2 Hz, 1H), 3.39
(m, 1H), 3.46 (dd, J1¼13.0 Hz, J2¼5.9 Hz, 1H), 3.68 (d, J¼15.5 Hz, 1H),
3.83 (dd, J1¼13.0 Hz, J2¼10.5 Hz, 1H), 4.37(m, 1H), 6.33 (d, J¼2.7 Hz,
1H), 6.72(d, J¼2.7 Hz, 1H), 6.91(d, J¼7.3 Hz, 2H), 7.37 (m, 8H). 13C
4.6.1.1. Data for 20. 19F (376 MHz, CDCl3):
(400 MHz, CDCl3):
d
ꢀ55.37. 1H NMR
d
2.40 (s, 3H), 3.38 (dd, J1¼14.6 Hz, J2¼4.4 Hz,
1H), 3.46 (dd, J1¼14.6 Hz, J2¼4.6 Hz, 1H), 3.81 (s, 3H), 3.84 (s, 3H),
5.26 (m, 1H), 6.26 (s, 1H), 6.78 (d, J¼3.7 Hz, 2H), 7.17 (m, 3H). 13C
NMR (100 MHz, CDCl3):
d 176.8, 174.6, 136.2, 131.4, 129.7, 129.4,
NMR (100 MHz, CDCl3):
d
163.0, 162.6, 135.6, 134.0, 131.7, 129.9 (q,
129.1(x2), 127.5, 126.5, 126.4 (q, JCeCeCF ¼3.67 Hz), 124.1 (q,
3
JCCeCF ¼3.7 Hz),129.3,128.5,127.4,123.9 (q, JCF ¼267.0 Hz),116.6 (q,
JCeCeCF ¼266.6 Hz), 117.3, 111.6 (q, JCeCeCF ¼36.4 Hz), 106.0
3
3
3
3
JCeCF ¼36.0 Hz), 102.0 (q, JCCeCF ¼2.9 Hz), 63.7, 52.8, 52.3, 37.2,
(q, JCeCeCF ¼2.9 Hz), 56.4, 42.7, 39.9, 34.3, 23.0. MS (EI): 424(Mþ,
3
3
3
11.52.
43%), 333(18%), 187(8%), 186(100%), 174(5%), 166(9%), 117(23%),
91(9%). HRMS (EI-TOF): calculated C24H19F3N2O2 [Mþ]: 424.1398.
Found: 424.1399.
4.6.1.2. Data for 21. 19F (376 MHz, CDCl3):
(400 MHz, CDCl3):
J1¼13.5 Hz, J2¼4.6 Hz, 1H), 3.79 (s, 3H), 3.89 (s, 3H), 3.92 (m, 2H),
5.34 (m, 1H), 6.42 (d, J¼2.6 Hz, 1H), 6.64 (d, J¼2.6 Hz, 1H), 6.65 (br
s, 2H), 7.17 (m, 3H)., HRMS (ESI-TOF): mixture of compounds 20
and 21: calculated C20H19F3NO4 [MþþH]: 394.12589. Found:
394.12607.
d
ꢀ55.07. 1H NMR
d
3.08 (dd, J1¼13.5 Hz, J2¼3.3 Hz, 1H), 3.23 (dd,
4.7. Computational study
All calculations were performed with the Gaussian09 program
system.9 Transition-state theory was used to evaluate the energy of
the different channels. The transition states were characterized by
the presence of one negative frequency and the internal reactions
coordinate (IRC) method was applied to verify that the correct
states were connected.
4.6.2. 4-Benzyl-2,6-dimethyl-7-trifluoromethyl-3a,4-dihydropyrrolo
[3,4-a]pyrrolizine-1,3(2H,8bH)-dione (22a) and 4-benzyl-2-methyl-
8-trifluoromethyl-3a,4,9,9a-tetrahydro-1H-pyrrolo[3,4-f]indolizine-
1,3(2H)-dione (23a). Isolated as a 28:72 mixture (determined by 1H
NMR), 88% yield.
Acknowledgements
Thanks are due to FCT (PEst-C/QUI/UI0313/2011), FEDER, COM-
PETE, and QREN for financial support. W.J.P. acknowledges the
National Scientific and Technical Research Council (CONICET) of
Argentina for the Post-Doctoral fellowship and Ana Julieta Pepino
for the assistance in the theoretical study.
4.6.2.1. Data for 22a. 19F (376 MHz, CDCl3):
(400 MHz, CDCl3):
d
ꢀ55.17. 1H NMR
d
2.35 (s, 3H), 2.89 (s, 3H), 3.06 (dd, J1¼14.2 Hz,
J2¼4.2 Hz,1H), 3.12 (dd, J1¼14.2 Hz, J2¼5.3 Hz,1H), 3.43 (d, J¼7.4 Hz,
1H), 3.61(d, J¼7.4 Hz, 1H), 5.00 (t, J¼4.6 Hz, 1H), 6.10 (s, 1H), 6.80 (d,
J¼6.6 Hz, 2H), 7.25 (m, 3H). 13C NMR (100 MHz, CDCl3):
d 177.07,
174.30, 134.3, 129.5, 129.0, 127.8, 127.6, 124.0 (q, JCCeCF ¼3.7 Hz),
3
Supplementary data
124.0 (q, JCF ¼266.7 Hz), 116.2 (q, JCeCF ¼35.5 Hz),
3
3
99.9(q, JCCeCF ¼3.7 Hz), 53.1, 25.4, 59.1, 43.5, 41.1, 10.8.
3
19F, 1H, and 13C NMR spectra for all new compounds and theo-
4.6.2.2. Data for 23a. 19F (376 MHz, CDCl3):
(400 MHz, CDCl3):
d
ꢀ54.55. 1H NMR
ꢁ
retical calculation results. Cartesian coordinates (A) obtained from
the B3LyP(6-31þG(d,p)) calculations. Supplementary data associ-
ated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2013.03.017.
d
2.83 (s, 3H), 2.98 (dd, J1¼15.8 Hz, J1¼7.2 Hz,1H),
3.20 (dd, J1¼9.2 Hz, J2¼3.8 Hz,1H), 3.26 (m,1H), 3.37(dd, J1¼13.4 Hz,
J2¼5.2 Hz, 1H), 3.52(d, J¼15.8 Hz, 1H), 3.76 (dd, J1¼13.4 Hz,
J2¼6.1 Hz, 1H), 4.31 (m, 1H), 6.24 (d, J¼2.6 Hz, 1H), 6.62 (d, J¼2.6 Hz,
1H), 7.34 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 177.7, 175.5, 136.2,
References and notes
129.6, 129.0, 127.4, 126.4 (q, JCeCeCF ¼3.67 Hz), 124.1(q,
3
1. Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827e856.
2. (a) Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G.
Synthesis 2009, 23, 3905e3929; (b) Saijo, R.; Hagimoto, Y.; Kawase, M. Org. Lett.
2010, 12, 4776e4779; (c) Saijo, R.; Kawase, M. Tetrahedron Lett. 2012, 53,
2782e2785.
JCeCeCF ¼266.8 Hz), 117.27, 111.6 (q, JCeCeCF ¼36.4 Hz), 105.9
3
3
(q, JCeCeCF ¼2.9 Hz), 56.2, 42.5, 39.4, 34.5, 25.1, 22.2.
3
HRMS (ESI-TOF): mixture of compounds 22a and 23a: calculated
C19H18F3N2O2 [MþþH]: 363.13254. Found: 363.13149.

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W.J. Pelaez, T.M.V.D. Pinho e Melo / Tetrahedron 69 (2013) 3646e3655
3655
3. (a) Black, B. C.; Hollingworth, R. M.; Ahammadsahib, K. Y.; Kukel, C. D.; Dono-
van, S. Pestic. Biochem. Physiol. 1994, 50, 115e128; (b) Zanatta, N.; Schneider, J.
M. F. M.; Schneider, P. H.; Wouters, A. D.; Bonacorso, H. G.; Martins, M. A. P.;
Essjohann, L. A. J. Org. Chem. 2006, 71, 6996e6998; (c) Dou, G.; Shi, C.; Shi, D. J.
Comb. Chem. 2008, 10, 810e813; (d) Uno, H.; Inoue, K.; Inoue, T.; Fumoto, Y.;
Ono, N. Synthesis 2001, 2255e2258; (e) Fitzgerald, J. P.; Nanda, H.; Fitzgerald, P.;
Yee, G. T. J. Org. Chem. 2000, 65, 2222e2224; (f) Funabiki, K.; Ishihara, T.;
Yamanaka, H. J. Fluorine Chem. 1995, 71, 5e7; (g) Zanatta, N.; Wouters, A. D.;
Fantinnel, L.; da Silva, F. M.; Barichello, R. Synlett 2009, 755e758; (h)
Korotaev, V. Yu; Barkov, A. Yu; Kotovich, I. V.; Sosnovskikh, V. Ya J. Fluorine
Chem. 2012, 138, 42e47.
5. (a) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Rocha Gonsalves, A. M. d’A. Tet-
rahedron Lett. 2006, 47, 791e794; (b) Pinho e Melo, T. M. V. D.; Soares, M. I. L.;
Nunes, C. M.; Paixao, J. A.; Matos Beja, A.; Ramos Silva, M. J. Org. Chem. 2007, 72,
~
4406e4415.
6. (a) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007,
63, 7753e7808; (b) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56,
7267e7272.
7. Ess, H.; Houk, K. N. J. Phys. Chem. A. 2005, 109, 9542e9553.
8. Soloway, H.; Kipnis, F.; Ornfelt, J.; Spoerri, P. E. J. Am. Chem. Soc. 1948, 70,
1667e1668.
9. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato,
M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Ioslowski, J.; Fox,
D. J. Gaussian 09, Revision B.01; Gaussian: Wallingford, CT, 2010.
4. (a) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Rocha Gonsalves, A. M. d’A.; McNab,
H. Tetrahedron Lett. 2004, 45, 3889e3893; (b) Pinho e Melo, T. M. V. D.; Soares,
~
M. I. L.; Rocha Gonsalves, A. M. d’A.; Paixao, J. A.; Matos Beja, A.; Ramos Silva, M.
J. Org. Chem. 2005, 70, 6629e6638; (c) Pinho e Melo, T. M. V. D.; Soares, M. I. L.;
Nunes, C. M. Tetrahedron 2007, 63, 1833e1841; (d) Soares, M. I. L.; Pinho e Melo, T.
M. V. D. Tetrahedron Lett. 2008, 49, 4889e4893; (e) Soares, M. I. L.; Lopes, S. M. M.;
Cruz, P. F.; Brito, R. M. M.;Pinho e Melo, T. M. V. D. Tetrahedron 2008, 64, 9745e9753;
(f) Pereira, N. A. M.; Serra, A. C.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2010,
6539e6543; (g) Pereira, N. A. M.; Fonseca, S. M.; Serra, A. C.; Pinho e Melo, T. M. V.
D.; Burrows, H. D. Eur. J. Org. Chem. 2011, 3970e3979; (h) Nunes, C. M.; Ramos Silva,
M.; Matos Beja, A.; Fausto, R.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2010, 51,
411e414.