Cycloaddition of trifluoromethyl azafulvenium methides: synthesis of new trifluoromethylpyrrole-annulated derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.11.033

The chemistry of trifluoromethyl azafulvenium methides was explored leading to a new route to trifluoromethylpyrrole-annulated systems. The first evidence of azafulvenium methides acting as 1,3-dipoles is reported. These azafulvenium methides showed site selectivity in the reaction with strong electron-deficient dipolarophiles leading exclusively to 1,3-cycloadducts. In the cycloaddition with less-activated dipolarophiles 1,7-cycloadducts resulting from [8π+2π] cycloaddition are also formed. FMO analysis of the cycloaddition reactions allowed the rationalization of the observed selectivity.

Full text of DOI:10.1016/j.tetlet.2009.11.033

Tetrahedron Letters 51 (2010) 411–414
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cycloaddition of trifluoromethyl azafulvenium methides: synthesis of new
trifluoromethylpyrrole-annulated derivatives
Cláudio M. Nunes a, Manuela Ramos Silva b, Ana Matos Beja b, Rui Fausto a, Teresa M. V. D. Pinho e Melo a,
*
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemistry of trifluoromethyl azafulvenium methides was explored leading to a new route to triflu-
oromethylpyrrole-annulated systems. The first evidence of azafulvenium methides acting as 1,3-dipoles
is reported. These azafulvenium methides showed site selectivity in the reaction with strong electron-
deficient dipolarophiles leading exclusively to 1,3-cycloadducts. In the cycloaddition with less-activated
Received 12 October 2009
Revised 6 November 2009
Accepted 10 November 2009
Available online 13 November 2009
dipolarophiles 1,7-cycloadducts resulting from [8
the cycloaddition reactions allowed the rationalization of the observed selectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
p+2p] cycloaddition are also formed. FMO analysis of
Keywords:
Trifluoromethylpyrroles
1,3-Dipoles
1,7-Dipoles
Azafulvenium methides
Azomethine ylides
[8p+2p] Cycloaddition
1,3-Dipolar cycloaddition
1,7-Electrocyclization
Microwave
Pyrroles represent an important class of heterocycles due to
their broad distribution in nature as constituents of the framework
of a range of natural products, and also of synthetic bioactive mol-
ecules.1 Polypyrroles also find applications in materials science,
nonlinear optics, and supramolecular chemistry as molecular sen-
sors and devices.2 On the other hand, the development of routes to
heterocyclic compounds bearing a trifluoromethyl group has re-
ceived much attention, since the introduction of this group with
unique stereoelectronic properties in organic molecules often im-
proves their biological activity. The influence of the trifluoromethyl
group on the physiological activity is usually concerned with the
increasing lipophilicity, leading to the improvement of their trans-
port characteristics in vivo. The high electronegativity of the CF3
group results in a quite different electron-density distribution
and significantly changes the reactivity of the molecules. There
are only a few examples of trifluoromethyl-containing pyrroles,
however, some of these compounds have demonstrated important
insecticidal action and mitochondrial uncoupling activity.3
derivatives studied up to now showed the reactivity pattern ex-
pected for 1,7-dipoles.4–7 It has been demonstrated that aza- and
diazafulvenium methides are very versatile building blocks for
the synthesis of functionalized pyrroles and pyrazoles. These
extended 1,7-dipoles are generated from 2,2-dioxo-1H,3H-pyrrol-
o[1,2-c]thiazoles (e.g., 3) or 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thia-
zoles (e.g., 4) by thermal extrusion of sulfur dioxide and
participate in pericyclic reactions, namely sigmatropic [1,8]H shifts
and 1,7-electrocyclizations, giving N-vinyl- or C-vinyl pyrroles and
pyrazoles.4–7 Azafulvenium methides 5 generated under micro-
wave irradiation from the corresponding 2,2-dioxo-1H,3H-pyrrol-
o[1,2-c]thiazoles can be intercepted in [8
p
+2p
] cycloadditions.7
1,7-dipoles under
Diazafulvenium methides 6 also behave as 8
p
either microwave irradiation or conventional heating, affording
the corresponding 1,7-cycloadducts 8 (Scheme 1).4,6,7
In this context, we decided to further explore the chemistry of
azafulvenium methides in order to find a new route to trifluorom-
ethylpyrrole-annulated systems.
Aza- and diazafulvenium methide systems 1 and 2 are reactive
intermediates which can be considered ‘higher-order’ azomethine
ylides and azomethine imines, respectively. These systems, in prin-
One approach to construct trifluoromethylated compounds,
including 7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, is the
use of halogen-containing building blocks as starting reagents.8 In
fact, it has been reported that the reaction of 4-ethyloxy-1,1,1-triflu-
orobut-3-ene-2-one (9)9 with thiazolidine-4-carboxylic acid (10a)
gives a mixture of pyrrolo[1,2-c]thiazoles, 7-(trifluoromethyl)-
1H,3H-pyrrolo[1,2-c]thiazole (11a) obtained as the major product,
ciple, could act as 4p 1,3-dipoles or as 8p 1,7-dipoles. However, the
* Corresponding author. Tel.: +351 239 854475.
E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.033

412
C. M. Nunes et al. / Tetrahedron Letters 51 (2010) 411–414
OEt
7
CO2H
NH
CO2H
5
6
1 X = CR Azafulvenium methide
4
2 N
2 X = N Diazafulvenium methide
S
S
N
CF3
X
3
ACN, r.t.
1
F3C
O
O
R
R
9
CO2Me
13a R = H 88%
13b R = Ph 85%
10a R = H
10b R = Ph
CO2Me
CO2Me
- SO2
CO2Me
O2S
R1
N
X
N
CF3
CF3
X
H2O2
Na2WO4
TFAA
ACN, r.t.
R1
S
O2S
3 X = CMe
4 X = N
N
35 ºC
N
5 X = CMe
6 X = N
R
R
[8π+2π] Cycloaddition
a
b
11a R = H 78%
11b R = Ph 85%
14a R = H 73%
14b R = Ph 70%
CO2Me
Scheme 3. Synthesis of 2,2-dioxo-7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thia-
zoles 14.
a
CO2Me
b
N
X
7 X = CMe
8 X = N
R1
mediate trifluoromethyl azafulvenium methides 15 which could
be trapped by dipolarophiles. We observed the first evidence of
azafulvenium methides acting as 1,3-dipole leading to 1,3-dipolar
cycloadducts. In fact, azafulvenium methides 15 react with N-
phenylmaleimide affording cycloadducts 1613 resulting from the
addition across the 1,3-position, and no 1,7-cycloadducts could
be detected.
In the case of trifluoromethyl azafulvenium methide 15b the
formation of C-vinylpyrrole 17 as a competitive reaction was also
observed. In the absence of dipolarophile the C-vinylpyrrole 17
was obtained exclusively in 64% yield (Scheme 4). The formation
of C-vinylpyrroles from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazole-
Scheme 1. [8p+2p] cycloaddition of aza- and diazafulvenium methides.
together with the formation of 1H,3H-pyrrolo[1,2-c]thiazole 12
(Scheme 2).10
In order to prepare our target 2,2-dioxo-7-(trifluoromethyl)-
1H,3H-pyrrolo[1,2-c]thiazoles we looked into this reaction of ke-
tone 9 with thiazolidines. The reaction of thiazolidines 10 with
4-ethyloxy-1,1,1-trifluorobut-3-ene-2-one (9) gave the expected
1-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]thiazolidines 13 in good
yield. Two rotamers are observed in the 1H NMR and 13C NMR
spectra of compounds 13 recorded at ambient temperature, but
the spectra recorded at 100 °C showed a single set of signals. It is
important to notice that 13b was obtained in a diastereoselective
fashion. This selectivity can be explained considering that 2-
unsubstituted-1,3-thiazolidine-4-carboxylates can undergo selec-
tive inversion at C-2 through a mechanism involving the opening
of the ring with the formation of the corresponding Schiff base,
but the N-protection of the 2-substituted-1,3-thiazolidine-4-car-
boxylates prevents this epimerization and allows the isolation of
pure diastereoisomers.11
We observed that by changing the solvent from dichlorometh-
ane to acetonitrile, the cyclization of enamines 13 gives almost
exclusively 7-(trifluoromethyl)-1H,3H-1H,3H-pyrrolo[1,2-c]thia-
zoles 11. The structure of product 11b was determined by X-ray
crystallography allowing to unambiguously establish the stereo-
chemistry as being R configuration (see Supplementary data). The
diffraction spectrum of the powder was also obtained and was
identical to the simulation of the diffraction spectrum for com-
pound 11b based on the X-ray diffraction data collected from the
single crystal. Therefore, we could confirm that 1-[(E)-4,4,4-tri-
fluoro-3-oxo-1-butenyl]thiazolidines 13b was obtained as a single
stereoisomer and underwent cyclization to give chiral (R)-3-phe-
R = H 70%
1,2,4-TCB, reflux, 6 h
CF3
CF3
F3C
Me
O
H
H
- SO2
O2S
1,3-DC
N
MW, 10-15 min
240-245 °C
1,2,4-TCB
N
N
N Ph
NPM
R = H
R
R
O
14a R = H
14b R = Ph
15a R = H
15b R = Ph
16a 72%
R = Ph
via 1,7-Electrocyclization
R = Ph
NPM
F3C
Me
F3C
F3C
CF3
O
N
O
H
H
N
Ph
Ph
N
H
N
N
H
Ph
Ph
H
Ph
16b 49%
17 64%
17 41%
Scheme 4. Pericyclic reactions of trifluoromethyl azafulvenium methides.
nyl-7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazole 11b
+159) in 85% yield (Scheme 3).
½ ꢀ
a D
CF3
F3C
Me
DMAD
CO2Me
CO2Me
O2S
MW, 10 min
240-245 °C
1,2,4-TCB
The
2,2-dioxo-7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thia-
N
N
zoles 14 were prepared in good yields by catalytic oxidation12 of
11 (Scheme 3).
18 61%
14a
Microwave irradiation of 2,2-dioxo-7-trifluoromethyl-1H,3H-
pyrrolo[1,2-c]thiazoles 14 led to the generation of the new inter-
MW, 10 min, 240-245 °C, 1,2,4-TCB
Ph CO2Et
7
F3C
6
CF3
8
5
1. r.t., ACN
2. TFAA,
r.t., DCM
CF3
CF3
1
Ph
CO2H
NH
10a
1
O
CF3
7
Ph
5
O
2
3
N
Me
S
S
6
4
S
N
4
N
N
2
3
CO2Et
EtO2C
CF3
OEt
12 14%
11a 52%
9
19
72 % (82:18)
20
Scheme 2. Synthesis of 7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazoles.10
Scheme 5. Cycloaddition reactions of 15a.

C. M. Nunes et al. / Tetrahedron Letters 51 (2010) 411–414
413
Table 1
Frontier orbital energies (eV) for 15a and different dipolarophiles at AM1, PM3 and HF/6-31G(d) theoretical levels
HOMO
PM3
LUMO
PM3
D
E(I)a
ꢁ
D
E(II)b
HF/6-31G(d)
AM1
HF/6-31G(d)
AM1
HF/6-31G(d)
AM1
PM3
15a
NPM
ꢁ7.83
ꢁ8.19
ꢁ6.15
ꢁ1.24
ꢁ1.25
ꢁ0.51
ꢁ0.67
ꢁ1.44
ꢁ1.22
ꢁ0.36
ꢁ0.66
1.40
1.51
3.01
2.25
—
—
—
ꢁ11.61
ꢁ11.96
ꢁ9.68
ꢁ11.49
ꢁ11.83
ꢁ9.72
ꢁ11.52
ꢁ11.72
ꢁ8.94
3.78
3.40
1.28
3.08
2.56
0.75
5.26
3.96
2.02
DMAD
Ethyl 3-phenylpropiolate
Isosurface of HOMO and LUMO of 15a and calculated MO coefficients (PM3) at the reactive sites C1, C3, and C7 are also presented.
a
D
D
E(I) = HOMOdipole ꢁ LUMOdipolarophile
b
E(II) = HOMOdipolarophile ꢁ LUMOdipole
6,7-dicarboxylates via 1,7-electrocyclization of the azafulvenium
methide intermediates has been observed previously.5
ing the 1,7-cycloaddition. This rationalization explains the forma-
tion of both 1,3-cycloadduct and 1,7-cycloadduct when the
reaction is promoted with ethyl 3-phenylpropiolate (Table 1 and
Supplementary data).
Storr et al. also carried out molecular orbital calculations (PM3)
to estimate the atomic orbital coefficients and the energy of the
HOMO and LUMO of azafulvenium methide 5 (R1 = H).4 The data
suggested that the addition of azafulvenium methide 5 to DMAD
should occur via 1,3-dipolar cycloaddition and the reaction with
The generation of trifluoromethyl azafulvenium methides 15
is also possible under conventional thermolysis. Heating at reflux
a solution of 1H,3H-pyrrolo[1,2-c]thiazole 14a and N-phenyl-
maleimide in 1,2,4-trichlorobenzene for 6 h leads to the forma-
tion of 1,3-cycloadduct 16a in 70% yield (Scheme 4). This result
is an indication that the generation of 5-trifluoromethyl azafulve-
nium methides 15 is easier than the generation of azafulvenium
methide derivatives previously studied, which required sealed
tube thermolysis, flash vacuum pyrolysis, or microwave irra-
diation.4,6
The trifluoromethyl azafulvenium methide 15a generated from
1H,3H-pyrrolo[1,2-c]thiazole 14a under microwave irradiation also
reacts with dimethylacetylene dicarboxylate to give the corre-
sponding 1,3-dipolar cycloadduct 18 in 61% yield. The reaction
with ethyl 3-phenylpropiolate gives a mixture of 1,3- and 1,7-cyc-
loadducts 19 and 20, respectively, in 72% overall yield with a ratio
of 82:18 (Scheme 5). The structural assignment of these cycload-
ducts was based on a NOESY spectrum. The spectrum of compound
19 shows connectivity between the phenyl group and the pyrrolic
proton and connectivity between the methyl group and the methy-
lenic protons can also be observed. In the NOESY spectrum of com-
pound 20, connectivity between methylenic protons H5 and the
pyrrolic proton H3 is observed. On the other hand, the methylenic
protons H8 are correlated with the phenyl group, which is in agree-
ment with the proposed structure. No reaction was observed using
bis(trimethylsilyl)acetylene, dimethyl azodicarboxylate, or N-ben-
zylidenebenzenesulfonamide as dipolarophiles.
electron-rich dipolarophiles would be via [8p+2p] mode. This pre-
diction suggests that this dipole 5 should have the same chemical
behavior toward dipolarophiles as the one shown by trifluoro-
methyl azafulvenium methide (15a). However, we observed that
azafulvenium methide 5 (R1 = H) shows site selectivity giving only
addition across the 1,7-positions with both electron-rich and elec-
tron-poor dipolarophiles.7 This selectivity can be explained consid-
ering that steric effects play an important role. In fact, dipole 5 has
a methyl substituent at C3 whereas the C3 position of azafulveni-
um methide 15a is unsubstituted.
In summary, we have described the generation of new transient
trifluoromethyl azafulvenium methides and their use as building
blocks for the construction of trifluoromethylpyrrole derivatives.
The first evidence of azafulvenium methides acting as 1,3-dipoles
is reported.
Acknowledgments
Thanks are due to FCT (PTDC/QUI/64470/2006 and SFRH/BD/
28844/2006) and FEDER for financial support. We acknowledge
the Nuclear Magnetic Resonance Laboratory of the Coimbra Chem-
ical Centre (www.nmrccc.uc.pt), University of Coimbra, for obtain-
ing the NMR data.
The FMO analysis for cycloaddition reactions of trifluoromethyl
azafulvenium methide 15a indicated that the HOMOdipole
-
LUMOdipolarophile is the dominant interaction for strong electron-
deficient dipolarophiles. In the HOMOdipole controlled reaction,
the reactive sites C1 and C3 of the dipole have the higher orbital
coefficients indicating that the 1,3-cycloaddition should take place
exclusively as observed experimentally. For the less-activated
Supplementary data
Synthetic procedures and characterization data for all com-
pounds. X-ray crystal structure of compound 11b and computa-
tional data are available. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.033.
dipolarophiles such as ethyl 3-phenylpropiolate, the LUMOdipole
–
HOMOdipolarophile interaction must also be considered. The LUMO
of the azafulvenium methide 15a is characterized by having the
reactive sites C1 and C7 with the highest orbital coefficients, favor-

414
C. M. Nunes et al. / Tetrahedron Letters 51 (2010) 411–414
7. Soares, M. I. L.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2008, 49, 4889–4893.
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suspension of 2,2-dioxo-7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazoles 14
(0.1 mmol) and dipolarophile (1.5–4 equiv) in 1,2,4-trichlorobenzene (0.5 mL)
was irradiated in the microwave reactor (CEM Focused Synthesis System,
Discover S-Class) with the temperature set to 240 °C for 10 min under stirring.
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chromatography with n-hexane to remove 1,2,4-trichlorobenzene followed
by elution with a mixture of ethyl acetate and n-hexane; (b) Stereochemistry
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