DAST promotes the synthesis of new 5-(trifluoromethyl)-3-(1,1-difluoroethan-2-yl)-1H-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2009.01.005

This study describes, firstly, the synthesis of a new precursor, 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one (1), from the trifluoroacetylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards, the reaction of 1 with two hydrazines (NH

Full text of DOI:10.1016/j.tetlet.2009.01.005

Tetrahedron Letters 50 (2009) 1392–1394
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DAST promotes the synthesis of new 5-(trifluoromethyl)-3-(1,1-difluoroethan-
2-yl)-1H-pyrazoles
*
Helio G. Bonacorso , Liliane M. F. Porte, Cleber A. Cechinel, Gisele R. Paim, Everton D. Deon,
Nilo Zanatta, Marcos A. P. Martins
Núcleo de Química de Heterociclos, NUQUIMHE, Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
This study describes, firstly, the synthesis of a new precursor, 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-
2-one (1), from the trifluoroacetylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards,
the reaction of 1 with two hydrazines (NH2NHR, where R = 2-furanoyl, C6F5) led to a new series of 4,5-
dihydro-1H-pyrazoles, containing an acetal-protected aldehyde function as substituent, in 90–97% yields.
In a subsequent step, the dehydration reactions of these 4,5-dihydro-1H-pyrazoles gave the respective
aromatic 1H-pyrazoles. Finally, we report the results of the deprotection reactions of the acetals to obtain
the respective aldehyde function, as well as, the subsequent fluorination reaction using DAST, leading to
new difluorinated derivatives in 55–60% yields.
Received 25 July 2008
Revised 30 December 2008
Accepted 6 January 2009
Available online 10 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
2ꢀ
Pyrazoles are important compounds that have many derivatives
with a wide range of interesting properties, such as anti-hypergly-
cemic, analgesic, anti-inflammatory, anti-pyretic, anti-bacterial,
and hypoglycemic and sedative-hypnotic activities.1 Many com-
pounds that present phenylpyrazoles in their structures are known
to have significant pharmacological activities, such as Celecoxib
(CelebraÒ), an anti-inflammatory that acts as a selective inhibitor
of the enzyme prostaglandin endoperoxide synthase-2 (PGHS-2),2
Fipronil, which belongs to a second generation of N-phenylpyraz-
oles3 insecticides, and sildenafil citrate (ViagraÒ), used against
erectile dysfunction.
Due to the importance of this class of compounds, since the
1980s we have developed synthetic routes to obtain strategically
substituted heterocycles that provide possibilities for chemical
derivatizations, leading to a substance, or its structural analogue,
with proven applications.4 The synthesis of pyrazoles that have a
protected aldehyde function as an acetal moiety, obtained in a sin-
gle-reaction step, deserves considerable attention, because this
substituent shows great chemical potential and serves as an inter-
mediary compound for a wide range of synthetic routes.
CF2–PO3 vs R–OPO32ꢀ). This functional group has been exten-
sively used in the design of inhibitors of enzymes that hydrolyze
or bind phosphate esters.6 The CF2 has been proposed as an ade-
quate isosteric and isopolar replacement for the hydroxyl group,
because of its size, electron distribution, and ability to act as a
hydrogen bond acceptor.7–9
Various research groups are developing CF3 containing substi-
tuted compounds, which have attracted considerable attention
due to their biological and pharmacological characteristics. The
influence of the trifluoromethyl substituent on physiological activ-
ity is due mainly to the increased lipophilicity of the molecules,
causing greater cell permeability.10
Moreover, compounds that have more than one CF3 group pres-
ent in the molecule are of even greater prominence, and have been
obtained fairly over the last few years. For example, 3,5-bis(trifluo-
romethyl) pyrazoles (BTP’s)11 are known as a new class of inhibi-
tors of cytokine. Furthermore, these compounds have also proven
useful in the treatment of autoimmune diseases and in the rejec-
tion of transplant organs.12,13
However, despite the importance of fluorine molecules, 1H-pyr-
azoles simultaneously containing trifluoromethyl and difluoroalkyl
substituents have not yet been described. So far, our research
group has conducted the introduction of fluorine atoms in hetero-
cyclic molecules through the employment of 1,3-dielectrophile tri-
fluoromethyl-substituted precursors from the reaction of
trifluoroacetylation of enol ethers or acetals with trifluoroacetic
anhydride.14
Due to the fact that the existing methods for direct fluorination
or trifluoroacetylation of organic compounds do not always allow
for the introduction of fluorine atoms at the desired position, ap-
proaches based on the use of synthetic precursors containing
The presence of difluoro- and trifluoromethyl substituents in
heterocycle rings is also of importance, because of the properties
presented by fluorine atoms. For example, in contrast to the single
replacement of a hydrogen by fluorine, the replacement of a meth-
ylene function with a difluoromethylene function (CH2 for CF2) can
have a significant effect on both conformation and physical proper-
ties.5 In fact, the difluoromethylene moiety has been used as an
electronic mimic of labile oxygen atoms in phosphate esters (R–
* Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.005

H. G. Bonacorso et al. / Tetrahedron Letters 50 (2009) 1392–1394
1393
fluorine are necessary. An alternate route is to use reagents that in
the first step transform the substituent into a good leaving group,
which will be replaced by fluorine in the second step. Within this
alternative proposal, one important and widely used reagent in
the fluorination of nucleosides, carbohydrates, and other organic
compounds is DAST (diethylaminosulfur trifluoride).15–17
fluoromethyl-1H-pyrazoles) demonstrating that DAST does not re-
act with the acetal function, even when it is connected to an
aromatic heterocycle, as in the case of compounds 3a–b. As the
5-trifluoromethyl-1H-pyrazoles (3a–b) did not react with DAST,
we sought alternative routes to achieve the difluorination of these
compounds. The method proposed herein is the deprotection of the
acetal function of the pyrazoline ring, leading to the corresponding
carbonyl compounds, and the subsequent introduction of fluorine
atoms into the molecules.
In order to isolate the carbonyl derivatives, an acetal deprotec-
tion reaction was carried out. Several methods were tested,19 and
the procedure described by Elisson et al.,20 using trifluoroacetic
acid in chloroform, showed the best results. This procedure, after
optimization, allowed attainment of 3-(formylmethyl)-5-trifluoro-
methyl-1H-pyrazoles (4a–b) in 55–65% yields.27,28 After obtaining
carbonyl compounds 4a–b, a difluorination step using DAST was
carried out in dichloromethane, at room temperature for 24 h,
leading to the isolation of difluorinated compounds 3-(1,1-difluo-
roethan-2-yl)-5-(trifluoromethyl)-1H-pyrazoles (5a–b) in 55–60%
yields (Scheme 2).29,30
With the intention of carrying out future biological evaluations,
it seemed desirable to develop a general method for the synthesis
of trifluoromethyl- and 1,1-difluoroethan-2-yl-1H-pyrazoles. Thus,
as an extension of our research program, we wish to report the first
regiospecific preparation of the precursor 4,6,6-trimethoxy-1,1,1-
trifluorohex-3-en-2-one (1) (Scheme 1), as well as, an alternative
and efficient route to obtain new trifluoromethyl-4,5-dihydro-
1H-pyrazoles, which contain an acetal-protected aldehyde
function, as substituent. In a subsequent step, the dehydration
reactions of 4,5-dihydro-1H-pyrazoles are reported, leading also
to protected 1H-pyrazoles. Finally, this study reports the deprotec-
tion of the acetal function to obtain the respective carbonyl
compounds and the subsequent fluorination reactions, using dieth-
ylaminosulfur trifluoride (DAST), leading to the difluorinated
analogues (Scheme 2).
An important feature in the 1H NMR spectra of compounds 5a–b
is the presence of a triplet in the region of 6.1–6.2 ppm, resulting
from the coupling of the H-7 with two fluorine atoms, with a con-
stant coupling of J = 55 Hz and with two hydrogen methylene
atoms, with a constant coupling of J = 5 Hz. Another feature is
the presence of a triplet of doublet in the region of 3.2–3.3 ppm
from the coupling of the H-6 (CH2) with two fluorine atoms (triplet
with J = 17 Hz) and with the atom of hydrogen H-7 (CHF2) (doublet
with J = 5 Hz).
4,6,6-Trimethoxy-1,1,1-trifluorohex-3-en-2-one (1) is a readily
available CCC synthetic block, and was prepared from the trifluoro-
acetylation reaction of 1,1,3,3-tetramethoxybutane, derived from
4,4-dimethoxybutan-2-one,
with
trifluoroacetic
anhydride
(Scheme 1).21,22
In this study, we found that 4,6,6-trimethoxy-1,1,1-trifluoro-
hex-3-en-2-one (1), when treated with hydrazines in a molar ratio
of 1:1, respectively, in ethanol as solvent for 4–20 h, at reflux, pro-
duced regiospecifically 3-(1,1-dimethoxyetan-2-yl)-5-hydroxy-5-
trifluoromethyl-4,5-dihydro-1H-pyrazoles (2a–b) in a one-step
reaction and in 90–97% yields (Scheme 2).23,24
The dehydration reaction of compounds 2a–b was carried out
by the methodology described by Padwa,18 which has the advan-
tage of obtaining heterocycles 3a–b25,26 while maintaining the
aldehyde group in the form of an acetal and also, in our case, pre-
venting the loss of the N1 substituent of the pyrazoline ring.
After the dehydration reaction of the 5-hydroxy-4,5-dihydro-
1H-pyrazoles (2a–b), we sought to carry out the difluorination of
the aromatic compounds 3a–b. However, the desired products
were not isolated. Instead, we isolated the starting material (5-tri-
As for the 13C{1H}NMR spectra for compounds 5a–b, the pres-
ence of a triplet in the region of 114 ppm for the CHF2 group with
a constant coupling of J = 241 Hz and another triplet in the region
of 33 ppm for the carbon C6, with J = 24 Hz, both resulting from the
C–F coupling at the difluoroethyl substituent.
In summary, we developed the first efficient and regiospecific
preparation of 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one
(1), a new precursor for the synthesis of a novel series of 1H-pyra-
zoles (2 and 3), which contain an acetal-protected aldehyde func-
tion as substituent. Moreover, a synthetic procedure that allowed
the regiospecific introduction of fluorine atoms was developed,
leading to the simultaneous obtainment of trifluoromethyl- and
difluoromethyl-substituted pyrazoles (5), in good yields.
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined on a Reichert
Thermovar apparatus, and are uncorrected. 1H and 13C NMR spec-
tra were acquired on a Bruker DPX 200 spectrometer (1H at
200.13 MHz and 13C at 50.32 MHz), 5 mm sample tubes, 298 K,
digital resolution 0.01 ppm, in DMSO-d6 for 2a and CDCl3 for 2b,
3a–b, 4a–b, 5a–b, using TMS as internal reference. The CHN ele-
O
OMe
O
OMe
OMe
i,ii
Me
OMe
F3C
OMe
1
Scheme 1. Reagents and conditions: (i) @HC(OMe)3, TsOH, MeOH, 24 h, rt (90%).
(ii) @(CF3CO)2, Py, CHCl3, 24 h, rt (65%).
H
OMe
OMe
OMe
H
F
O
OMe
OMe
OMe
O
F
HO
iv
iii
N
N
i
N
N
ii
55-60% F C
55-65% F C
72-85% F C
3
3
3
N
N
N
N
90-97%
OMe
F3C
F3C
R
R
R
R
1
2a-b
4a-b
3a-b
5a-b
2-5
R
a
b
2-furanoyl
C6F5
Scheme 2. Reagents and conditions: (i) @NH2NHR, EtOH, 4–20 h, reflux. (ii) @SOCl2, Py, benzene, 1 h, 0–25 °C. (iii) @CF3COOH, H2O, CHCl3, 4 h, 30 °C; (iv) @DAST, CHCl2,
24 h, rt.

1394
H. G. Bonacorso et al. / Tetrahedron Letters 50 (2009) 1392–1394
(C-4), 178.6 (q, 2J = 33, C-2), 118.2 (q, CF3, J = 292), 101.5 (C-6), 92.2 (C-3), 56.6
(C-6a-b), 53.1 (C-4a), 37.6 (C-5).MS: m/z (%) = 211 (66), 179 (71), 141 (36), 75
(100).Anal. Calcd: C, 44.63; H, 5.41. Found: C, 44.85; H, 5.13.
mental analyses were performed on a Perkin Elmer 2400 CHN ele-
mental analyzer (São Paulo University—USP/Brazil). Mass spectra
were registered in a HP 5973 MSD connected to a HP 6890 GC
and interfaced by a Pentium PC. The GC was equipped with a
split-splitless injector, autosampler, cross-linked HP-5 capillary
column (30 m, 0.32 mm of internal diameter), and He was used
as the carrier gas.
23. Synthesis of 3-(1,1-dimethoxyethan-2-yl)-5-hydroxy-5-trifluoromethyl-4,5-
dihydro-1H-pyrazole (2a–b). General procedure: A stirred solution of 4,6,6-
trimethoxy-1,1,1-trifluorohex-3-en-2-one (1) (2 mmol) with hydrazine
(2 mmol) in 15 mL of dry ethanol was stirred at 80 °C for 4 h (2b) and 20 h
(2a). After the reaction time, the solvent was removed under reduced pressure,
and the products were dried under vacuum, and isolated as a solid (2a) and an
oil (2b) (yields 90–97%).
24. Compounds 2a–b were characterized by 1H and 13C NMR. Spectral NMR data of
compound 2a: 1H NMR (DMSO) d = 7.9 (s, 1H, OH), 7.9 (s, 1H, H-50), 7.5 (d, 1H,
J = 3.0, H-30), 6.7 (m, 1H, H-4’), 4.7 (t, 1H, J = 6.0, H-7), 3.4 (d, 1H, J = 19, H-4a),
3.3 (s, 6H, H-7a-b), 3.1 (d, 1H, J = 19, H-4b), 2.7 (d, 2H, J = 6.0, H-6). 13C NMR
(DMSO) d = 155.2 (C@O), 154,1 (C-3), 146.6 (C-20), 145.4 (C-50), 123.3 (q, CF3,
J = 286), 120.1 (C-30), 111.8 (C-40), 101.1 (C-7), 91.3 (q, 2J = 33, C-5), 52.9 (C-7a-
b), 46.3 (C-4), 32.2 (C-6).MS: m/z (%) = 305 (20), 95 (97), 75 (100), 47 (47).Anal.
Calcd: C, 46.43; H, 4.50; N, 8.33. Found: C, 46.95; H, 4.46; N, 8.49.Melting
points and yields of new compounds 2: Compd. [Mp (°C), Yield (%)]: Compound
2a [120–122, 97]; Compound 2b [oil, 90].Melting points and yields of new
compounds 2: Compd. [Mp (°C), Yield (%)]: Compound 2a [(120–122), 97]; 2b
[(oil), 90].
Acknowledgments
The authors are thankful for the financial support from Conse-
lho Nacional de Desenvolvimento Científico e Tecnológico—CNPq.
Fellowships from Coordenação De Aperfeiçoamento de Pessoal de
Nível Superior—CAPES are also acknowledged.
References and notes
25. Synthesis of 3-(1,1-dimethoxyethan-2-yl)-5-trifluoromethyl-1H-pyrazole (3a–
b). General procedure: A solution of 3-(1,1-dimethoxyethan-2-yl)-5-hydroxy-
5-trifluoromethyl-4,5-dihydro-1H-pyrazole (2a–b) (2.6 mmol) and pyridine
(33.8 mmol) in 50 mL of benzene was cooled to 0 °C, and thionyl chloride
(16.8 mmol) diluted in 25 mL of benzene was added dropwise over 10 min. The
solution was stirred for an additional 30 min, during which time the
temperature was allowed to rise to 20 °C. The mixture was then heated
under reflux (bath temperature 80 °C) for 1 h, and was then filtered to remove
the pyridine hydrochloride at room temperature. The solution was washed
twice with water and dried over sodium sulfate. The solvent was evaporated,
obtaining dark oils as pure compounds (3a–b). (yields 75–85%).
1. Karci, F. Dyes Pigments 2008, 76, 97.
2. Penning, T. D. J. Med. Chem. 1997, 40, 1347.
3. Stevens, M. M.; Helliwell, S.; Warren, G. N. Field Crops Res. 1998, 57, 195.
4. (a) Milano, J.; Marchesan, S.; Rossato, M. F.; Sauzem, P. D.; Machado, P.; Beck,
P.; Zanatta, N.; Martins, M. A. P.; Mello, C.; Rubin, M. A.; Ferreira, J.; Bonacorso,
H. G. Eur. J. Pharmacol. 2008, 581, 86; (b) Zanatta, N.; Alves, S.; Coelho, H.;
Borchhardt, D. M.; Machado, P.; Flores, K. M.; Silva, F. M.; Spader, T. B.; Santurio,
J. M.; Bonacorso, H. G.; Martins, M. A. P. Bioorg. Med. Chem. 2007, 15, 1947; (c)
Cunico, W.; Cechinel, C. A.; Bonacorso, H. G.; Martins, M. A. P.; Zanatta, N.;
Souza, M.; Freitas, I.; Soares, R.; Kretlli, A. Bioorg. Med. Chem. Lett. 2006, 16, 649;
(d) Obregon, A.; Schetinger, M. R.; Correa, M.; Morsch, V.; Silva, J.; Martins, M.
A. P.; Zanatta, N.; Bonacorso, H. G. Neurochem. Res. 2005, 30, 379.
5. O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 7, 645.
6. Resnati, G. Farmaco 1990, 45, 1137.
7. Bergston, D. E.; Shum, P. W. J. Org. Chem. 1988, 53, 3953.
8. Bergston, D. E.; Mott, A. W.; Declercq, E.; Balzarini, J.; Swartling, D. J. J. Med.
Chem. 1992, 35, 3369.
9. Blackburn, G. M.; Eckstein, F.; Kent, D. E.; Perree, T. D. Nucleosides, Nucleotides
Nucleic Acids 1985, 4, 165.
26. Compounds 3a–b were characterized by 1H and 13C NMR. Spectral NMR data of
compound 3a: 1H NMR (CDCl3) d = 7.9 (d, 1H, J = 4.0, H-50), 7.7 (s, 1H, H-30), 6.8
(s, 1H, H-4), 6.6 (m, 1H, H-40), 4.7 (t, 1H, J = 6.0, H-7), 3.4 (s, 6H, H-7a-b), 3.0 (d,
13
2H, J = 6.0, H-6). C NMR (CDCl3) d = 153.7 (C@O), 151.3 (C-3), 148.5 (C-20),
2
144.4 (C-50), 135.2 (q, J = 41 Hz, C-5), 124.9 (C-30), 120.5 (q, CF3, J = 269 Hz),
113.9 (C-40), 112.5 (C-4), 102.8 (C-7), 53.4 (C-7a-b), 32.1 (C-6).MS: m/z
(%) = 287 (20), 149 (12), 95 (93), 75 (100).Anal. Calcd: C, 49.06; H, 4.12; N, 8.80.
Found: C, 48.91; H, 4.22; N, 9.19.Yields of new compounds 3: Compd. [Mp (°C),
Yield (%)]: Compound 3a [oil, 75]; Compound 3b [oil, 85].
10. Balenkova, E.; Druzhinin, S.; Nenajdenko, V. Tetrahedron 2007, 63, 7753.
11. Threadgill, M. D.; Herr, A. K.; Jones, B. G. J. Fluorine Chem. 1993, 65, 21.
12. Chen, Y. W.; Smith, L. M.; Chiou, X. G.; Ballaron, E.; Sheets, M.; Gubbins, E.;
Warrior, U.; Wilkins, J.; Surowy, C.; Nakane, M.; Carter, G.; Trevillyan, J. M.;
Mollison, K.; Djuric, S. Cell. Immunol. 2002, 220, 1345.
13. Djuric, S.; BaMaung, N.; Basha, A.; Liu, H.; Luly, J.; Madar, D.; Sciotti, R.; Tu, N.;
Zhou, X.; Ballaron, S.; Mollison, K.; Sheets, M.; Smith, M.; Trevillyan, J.; Warrior,
U.; Wegner, C.; Carter, G. J. Med. Chem. 2000, 43, 2975.
14. (a) Bonacorso, H. G.; Wentz, A.; Lourega, R.; Cechinel, C. A.; Moraes, T.; Coelho,
H.; Zanatta, N.; Martins, M. A. P.; Horner, M.; Alves, S. J. Fluorine Chem. 2006,
127, 1066; (b) Bonacorso, H. G.; Cechinel, C. A.; Oliveira, M. R.; Costa, M. B.;
Martins, M. A. P.; Zanatta, N.; Flores, A. F. C. J. Heterocycl. Chem. 2005, 42, 1055;
(c) Bonacorso, H. G.; Oliveira, M. R.; Costa, M. B.; Silva, L. B.; Wastowski, A. D.;
Zanatta, N.; Martins, M. A. P. J. Heterocycl. Chem. 2005, 42, 631.
27. Synthesis of 3-(formylmethyl)-5-trifluoromethyl-1H-pyrazole (4a–b). General
procedure: A stirred solution of 3-(1,1-dimethoxyethan-2-yl)-5-trifluoromethyl-
1H-pyrazole (3a–b) (2 mmol) in 8 mL of chloroform is added to an 4 mL aqueous
solution of trifluoroacetic acid (1:1). The solution was stirred for 4 h at 30 °C, and
was then washed twice with water and dried over sodium sulfate. The solvent
was evaporated, obtaining a yellow solid (4a) or a dark oil (4b), as pure
compounds.
28. Compounds 4a–b were characterized by 1H and 13C NMR. Spectral NMR data of
compound 4a: 1H NMR (CDCl3) d = 9.9 (t, 1H, J = 2.0, H-7), 7.9 (d, 1H, J = 4.0, H-
50), 7.7 (s, 1H, H-30), 6.9 (s, 1H, H-4), 6.6 (m, 1H, H-40), 3.9 (d, 2H, J = 2.0, H-6).).
13C NMR (CDCl3) d = 196.2 (CH@O, C-7), 153.6 (C@O), 148.9 (C-3), 147.1 (C-20),
144.2 (C-50), 135.7 (q, 2J = 41, C-5), 125.2 (C-30), 120.8 (q, CF3, J = 269), 113.8 (C-
40), 112.7 (C-4), 42.5 (C-6).MS: m/z (%) = 244 (10), 216 (4), 95 (100).Anal. Calcd:
C, 48.54; H, 2.59; N, 10.29. Found: C, 48.63; H, 2.78; N, 10.04.Melting points
and yields of new compounds 4: Compd. [Mp (°C), Yield (%)]: Compound 4a
[123–124, 55]; Compound 4b [oil, 65].
15. Baptista, L.; Bauerfeldt, G. F.; Arbilla, G.; Silva, E. C. J. Mol. Struct. 2006, 761, 73.
16. Middleton, W. J. J. Org. Chem. 1975, 40, 574.
17. Hudlicky, M. Org. React. 1987, 35, 513.
18. Padwa, A. J. Org. Chem. 1965, 30, 1274.
29. Synthesis of substituted 3-(1,1-difluoroethan-2-yl)-5-(trifluoromethyl)-1H-
pyrazoles (5a–b). General procedure: To a stirred solution of 3-(formylmethyl)-
5-trifluoromethyl-1H-pyrazole (4a–b) (2 mmol) in dichloromethane (10 mL) was
added dropwise DAST (4 mmol) in dichloromethane (5 mL) at ꢀ5 °C. The reaction
mixture was stirred at 25 °C for 24 h, and then the reaction was quenched by the
slow addition of aqueous NaHCO3 solution until effervescence was complete. The
dichloromethane layer was separated, dried over anhydrous NaCO3, and filtered.
The solvent was evaporated, obtaining a yellow solid (5a) and dark oil (5b).
Compound 5a was recrystallized from diethylether and compound 5b was purified
by chromatography on silica, using an ethyl acetate and hexane mixture.
30. Compounds 5a–b were characterized by 1H and 13C NMR. Spectral NMR data of
compound 5a: 1H NMR (CDCl3) d = 7.8 (d, 1H, J = 4.0, H-50), 7.8 (s, 1H, H-30), 6.9
(s, 1H, H-4), 6.6 (m, 1H, H-40), 6.2 (1H, tt, JHF = 55, JHH = 5.0, CHF), 3.3 (2H, td,
JHF = 17, JHH = 5.0, H-6). 13C NMR (CDCl3) d = 153.6 (C@O), 148.9 (C-3), 147.3 (C-
20), 144.2 (C-50), 135.8 (q, 2J = 41, C-5), 125.2 (C-30), 119.8 (q, CF3, J = 269), 114.6
(t, CF2, J = 241), 113.6 (C-4), 112.7 (C-40), 33.7 (C-6).MS: m/z (%) = 294 (M+, 5),
266 (70), 188 (5), 95 (100).Anal. Calcd: C, 44.91; H, 2.40; N, 9.52. Found: C,
44.63; H, 2.51; N, 9.47.Melting points and yields of new compounds 5: Compd.
[Mp (°C), Yield (%)]: Compound 5a [128–130, 55]; Compound 5b [oil, 60].
19. (a) Li, C.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565; (b) Keana, J.; Little, G.
Heterocycles. 1983, 7, 1291; (c) Price, S.; Bordogna, W.; Bull, R.; Clark, D.; Dyke,
H.; Harris, N.; Mullett, J.; White, A. Bioorg. Med. Chem. Lett. 2007, 17, 370.
20. Ellison, R.; Lukenbach, E.; Chiu, C. Tetrahedron Lett. 1975, 8, 499.
21. Synthesis of 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one (1). General
procedure: To an ice-cold stirred mixture of 1,1,3,3-tetramethoxybutane
(30 mmol), pyridine (60 mmol), and anhydrous chloroform (30 mL) was
added dropwise pure trifluoroacetic anhydride (60 mmol), and after
completion of the slow addition, the mixture was stirred for 24 more hours
at room temperature. Then, the mixture was washed with aqueous solution of
hydrochloric acid 0.1 M (3 ꢁ 15 mL) and water (2 ꢁ 15 mL), and was dried with
magnesium sulfate. The solvent was evaporated to give the practically pure
products 3. The pure compound was obtained by distillation under reduced
pressure (65% yield).
22. Compound 1 was characterized by 1H and 13C NMR. Spectral NMR data of
compound 1: 1H NMR (CDCl3) d = 5.7 (s, 1H, H-3), 4.7 (t, 1H, J = 6.0, H-6), 3.8 (s,
3H, H-4a), 3.3 (s, 6H, H-6a-b), 3.1 (d, 2H, J = 6.0, H-5) 13C NMR (CDCl3) d = 179.6