One-pot synthesis of a new series of 3-alkoxy-5-hydroxy-5-trifluoromethyl-pyrrolidin-2-ones from 1,1,1-trifluoro-4-alkoxyalk-3-en-2-ones

Article abstract of DOI:10.1055/s-2002-35217

The synthesis of a new series of 3-alkoxy-5-hydroxy-5-trifluoromethyl pyrrolidin-2-ones 2a-h from the reaction of 1,1,1-trifluoro-4-alkoxyalk-3-en-2-ones 1a-h of the general formula F₃CC(O)C(R²)=C(R¹)OR, where: R = Me, Et, -(CH₂)₂-, -(CH₂)₃-; R¹ = H, Me, Ph, p-Me-Ph, p-F-Ph; and R² = H, Me, -(CH₂)₂-, -(CH₂)₃- with sodium cyanide in hydro-alcoholic medium is reported.

Full text of DOI:10.1055/s-2002-35217

2404
PAPER
One-Pot Synthesis of a New Series of 3-Alkoxy-5-hydroxy-5-trifluoromethyl-
pyrrolidin-2-ones from 1,1,1-Trifluoro-4-alkoxyalk-3-en-2-ones
O
ne Pot Synthesis
i
of 3-A
l
lkoxy-5
o
-hydroxy-5-trifluo
Z
romethylpyrroli
a
din-2-onesnatta,* Luciana S. Rosa, Maria F. M. Cortelini, Simone Beux, Ana P. D. Santos, Helio G. Bonacorso,
Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.
105-900, Santa Maria, RS, Brazil
Fax +55(55)2208031; E-mail: zanatta@base.ufsm.br
Received 28 September 2001; revised 27 August 2002
ing blocks for the synthesis of corrins and related
Abstract: The synthesis of a new series of 3-alkoxy-5-hydroxy-5-
ligands.20 Corrins are molecules capable of complexing
trifluoromethyl pyrrolidin-2-ones 2a–h from the reaction of 1,1,1-
metals such as cobalt to form B12 vitamin and analogous
trifluoro-4-alkoxyalk-3-en-2-ones 1a–h of the general formula
compounds.21 A pyrrolidin-2-one derivative is also found
F3CC(O)C(R2)=C(R1)OR, where: R = Me, Et, -(CH2)2-, -(CH2)3-;
R1 = H, Me, Ph, p-Me-Ph, p-F-Ph; and R2 = H, Me, -(CH2)2-, as a constituent of the peptide histrelin that has been used
-(CH2)3- with sodium cyanide in hydro-alcoholic medium is report-
for the treatment of the precocious puberty showing supe-
rior activity than the commonly used hormones.22 More
ed.
Key words: ketones, pyrrolidin-2-ones, lactams, heterocycles,
fluorine
recently, N-substituted 5-methyl-5-trifluoromethylpyrrol-
idin-2-ones were claimed to function as cognitive perfor-
mance enhancers.23,24
Considering some of the important aspects summarized
above concerning pyrrolidin-2-ones, we wish to report the
synthesis of a new series of 5-hydroxy-5-trifluorometh-
ylpyrrolidin-2-ones 2a–h from the reaction of 1,1,1-tri-
fluoro-4-alkoxyalk-3-en-2-ones 1a–h with sodium
cyanide in hydro-alcoholic medium. The synthetic poten-
tial of compounds 1 to yield a series of heterocycles of
five,25–31 six,32–36 and seven membered rings,37,38 and in
Michael type reaction,39 has been shown in previous pub-
The presence of trifluorinated groups in organic mole-
cules was shown to induce special chemical, physical and
biological properties to these molecules largely due to the
elevated electronegative and lipophilic character of fluor-
ine atoms. As a consequence, in recent years much atten-
tion has been devoted to the synthesis of trifluorinated
compounds1–11 and many have proven to be of important
therapeutic value.12,13
In a recent publication, the synthesis of 3-ethoxy-5-hy- lications of our group.
droxy-5-trifluoromethylpyrrolidin-2-one from the reac-
The synthesis of a series of 5-trifluoromethylpyrrolidin-2-
tion of 1,1,1-trifluoro-4,4-diethoxy-2,2-diol and sodium
cyanide in ethanol, was reported.14 Lately we discover
that ketones 1a–h also react with sodium cyanide in hy-
dro-alcoholic medium furnishing 3-alkoxy-5-hydroxy-5-
trifluoromethylpyrrolidin-2-ones 2a–h, in a one pot reac-
tion. However, the reaction of related 4-alkoxyvinyl ke-
tones with trimethylsilyl cyanide has been shown by
Gerus et al.4 to undergo 1,2- and 1,4-addition of the trim-
ethylsilyl cyanide to the 4-alkoxyvinyl ketones giving the
corresponding open chain 1,2- and 1,4-trimethylsilyloxy
nitrile adducts instead of pyrrolidinones.
ones 2a–h was carried out from the reaction of ketones
1a–h with sodium cyanide in hydro-alcoholic medium, at
room temperature, according to Scheme 1.
The ketones 1a–h were dissolved in methanol or ethanol
and to this mixture a solution of sodium cyanide in water
was added at room temperature. In order to try to improve
the yields and/or the stereoselectivity, the reactions were
Pyrrolidin-2-ones have been the subject of very few stud-
ies, if compared to pyrroles, largely due to a lack of a sim-
ple general method of synthesis.15–19 The synthesis of
pyrrolidin-2-ones closely related to the method presented
in this work was reported by Stevens et al. in 1971.20 This
method relies on the reaction of 4-methylpent-3-en-2-one
with potassium cyanide in methanol to obtain a mixture of
5-hydroxy-3,3,5-trimethylpyrrolidin-2-one and 5-cyano-
3,3,5-trimethylpyrrolidin-2-one which were used a build-
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2404,2408,ftx,en;M05001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 1

PAPER
One Pot Synthesis of 3-Alkoxy-5-hydroxy-5-trifluoromethylpyrrolidin-2-ones
2405
carried out at different temperatures ranging from 0 °C to pounds in water. Yields, selected physical and spectral
the reflux of the solvent. Different solvents such as alco- data are presented in Table 1.
hols and THF were used. However, the most satisfactory
condition was found when alcohols were used as solvent
The pyrrolidinones 2a,b,f–h have two asymmetric car-
bons and two diastereoisomers were formed. The reac-
with the reaction carried out at room temperature. The re-
tions showed little stereoselectivity giving a pair of
action times were very dependent of the structure of the
stereoisomers in a ratio of approximately 60:40% as deter-
ketones 1a–h, ranging from 4 hours for 1a–d, 16 hours for
mined from both 1H NMR integrals and GC/MS. The mix-
1e,g, to 22 and 48 hours for the ketones 1h,f. The only iso-
lated products were the 3-alkoxy-5-hydroxy-5-trifluo-
romethylpyrrolidin-2-ones 2a–h. Surprisingly, com-
pounds 2a–h resisted the dehydration under various con-
ture of diastereoisomers were confirmed by the
observation of two sets of signals in both 1H and 13C NMR
spectra and two chromatographic peaks with different re-
tention times but with superimposed mass spectra in the
GC/MS. The minor isomer of the pyrrolidinone 2h was
ditions and an efficient method to convert them to the cor-
responding 5-trifluoromethyl-2-hydroxypyrroles, was not
lost during the crystallization process. The reactions,
yet found.
however, were highly regioselective furnishing only the
The products were isolated by extraction of the reaction pyrrolidinones 2 with the exclusion of 4-alkoxy-5-imino-
mixture with dichloromethane and the organic phase dried 2-trifluoromethyltetrahydrofuran-2-ols.40
with anhydrous magnesium sulfate. Compounds 2a–d
were obtained as light yellow oils and compounds 2e–h as
solids. The solids were purified by recrystallization and
the oils, which were isolated in satisfactory purity, were
analyzed without further purification. Tentative purifica-
tion of 2a–d by silica column chromatography was not
very successful.
According to Stevens et al.,20 the formation of 3-alkoxy-
The pyrrolidinones 2c–e have three asymmetric carbons,
and four diastereoisomers could be formed. Indeed, com-
pound 2c showed to be comprised of 4 stereoisomers in a
ratio of 60:30:8:2 determined by GC/MS, but 2e showed
three stereoisomers in a ratio of 60:34:6 and 2d exhibited
only a single compound.
A NOESY experiment of 2d showed a strong cross peak
between H-3 and H-4. This indicates that H-3 and H-4 are
close in space, which suggests that the pyrrolidinone ring
closure was accomplished with cis configuration with re-
5-hydroxy-5-trifluoromethylpyrrolidin-2-ones 2a–h pos-
sibly resulted from a Michael addition of the cyanide ion
to the -carbon of ketones 1a–h forming -cyano ketone
spect to the tetrahydrofuran ring. The coupling constant of
intermediates which were not isolated. Subsequent hy-
H-3 and H-4 of 7.8 Hz further supports this conclusion. So
drolysis of the cyano group to amide followed by an in-
the most probable structure for 2d presents the pyrrolidi-
tramolecular attack of the amide nitrogen to the
-
none ring closure in cis configuration with respect to the
tetrahydrofuran ring and the CF3 group is cis to the H-4
and trans to the CH2 of the tratrahydrofuran moiety.
trifluoro carbonyl furnished the compounds 2a–h in mod-
erate to good yields. The low yields observed for some
products may be due to the partial solubility of these com-
1
The mixture of isomers made the H NMR spectra very
complex. The 13C NMR spectra, however, were simpler
Table 1 Reaction Times and Selected Physical and Spectral Data for 2a–ha
Com-
pound
Reaction Yieldb
Time (h) (%)
Mpb (°C)
IRc ( cm–1)
MSd (%), EI (70 ev)
2a
2b
2c
2d
2e
2f
4
4
48
65
73
74
48
62
55
42
oil
3250, 1717
3180, 1703
3237, 1731
3282, 1732
3441, 1720
3284, 1690
3285, 1717
3239, 1716
169 (100), 100 (50), 73 (18), 56 (38)
oil
183 (100), 155 (17), 101 (22), 72 (43)
4
oil
183 (94), 168 (100), 114 (20), 70 (59)
4
oil
211 (12), 164 (63), 99 (100), 71 (97)
16
48
16
22
146–148
181 (100), 169 (34), 125 (29), 83 (29),
128–132e, 150–154f
152–155e, 189–191f
158–160
245 (100), 231 (37), 133 (24), 105 (46), 103 (41), 77 (31)
257 (42), 188 (100), 142 (40), 115 (34)
263 (100), 249 (24), 151 (28), 123 (59), 121 (42), 95 (19)
2g
2h
a Satisfactory elemental analysis C 0.50, H 0.40, N 0.40, except for: 2a, C 0.6; 2c, C 1.1, H 0.7; 2f, H 0.5; 2g, H 0.7.
b Yields of compounds 2a–d after extraction and yields of 2e–f after recrystallization.
c Stretching frequencies of OH/NH and C=O, respectively.
d Compounds 2a,c,e showed M – 44 (MOEt) while 2b,f–h showed M – 30 (M – OMe) as the molecular ion.
e Melting point for the minor isomer.
f Melting point for the major isomer.
Synthesis 2002, No. 16, 2404–2408 ISSN 0039-7881 © Thieme Stuttgart · New York

2406
PAPER
Table 2 1H NMR Spectral Data of Compounds 2a–h
and very useful to assign these structures. All compounds
1
have been fully analyzed by H and 13C NMR as well as
Com-
pound
1H NMR,a , J (Hz)
2D experiments41 such as COSY-HH, HMQC and HMBC
to provide unambiguous assignments of the mixture of
2ab
1.23 (t, 3 H, 3JHH = 7.0, CH3), 2.15 (dd, H, 2JH4 –H4 = 14.4,
1
isomers. H NMR spectral data of 2a–h are presented in
2
3JH4 –H3 = 8.0, H-4 ), 2.93 (dd, 1 H, JH4–H4 = 14.4,
Table 2 and their 13C NMR spectral data are presented in
Table 3. The NMR data of the two minor isomers of 2c
(2c and 2c ) and the minor isomer of 2e (2e ) were not
presented because the low signal to noise ratio did not al-
low the correct assignment.
3JH4–H3 = 8.0 Hz, H-4), 3.60–3.80 (m, 2 H, OCH2), 4.14 (t,
1 H, 3JH3–H4H4 = 8.0, H-3), 8.40 (s, 1 H, OH), 9.41 (br s, 1
H, NH)d
2a
1.23 (t, 3 H, 3JH–H = 7.0, CH3), 2.29 (dd, 1 H, 2JH4 –H4
=
14.4, 3JH4 –H3 = 8.0, H-4 ), 2.57 (dd, 1 H, 2JH4–H4 = 14.4,
3JH4–H3 = 8.0, H-4), 3.60–3.80 (m, 2 H, OCH2), 4.40 (t, 1
H, 3JH3–H4H4 = 8.0, H-3), 8.32 (s, 1 H, OH), 9.41 (br s, 1 H,
NH)d
Unless otherwise indicated all common reagents and solvents were
used as obtained from commercial suppliers without further purifi-
cation. The 1,1,1-trifluoro-4-alkoxy-alk-3-en-2-ones (1) were pre-
pared according to references.26,42 Mps were determined on a
Reichert Thermovar apparatus and are uncorrected. 1H, 13C and 2D-
NMR spectra were acquired on a Bruker DPX 400 spectrometer (1H
at 400.13 MHz and 13C at 100.62 MHz) or on a Bruker DPX 200
spectrometer (1H at 200.13 MHz and 13C at 50.32 MHz) in CDCl3
or DMSO-d6, using TMS as the internal reference. IR spectra were
recorded on a Bruker IFS 28 FT-IR spectrometer in film for the oils
and KBr disks for the solid compounds. Elemental analysis was per-
formed on a Vario EL Elementar Analysensysteme. Mass spectra
were registered on a HP 5973 MSD connected to a HP 6890 GC and
interfaced by a pentium PC. The GC was equipped with a split-split-
less injector, autosampler, cross-linked HP-5 capillary column (30
m, 0.32 mm of internal diameter), and helium was used as the car-
rier gas.
2bc
2b
1.27 (s, 3 H, CH3), 1.98 (d, 1 H, 2JH4 –H4 = 15.5, H-4 ), 2.41
(d, 1 H, 2JH4–H4 = 15.5, H-4), 3.20 (s, 3 H, OCH3), 7.30 (br
s, 1 H, OH), 9.20 (br s, 1 H, NH)d
1.39 (s, 3 H, CH3), 1.72 (d, 1 H, 2JH4 –H4 = 14.5, H-4 ), 2.56
(d, 1 H, 2JH4–H4 = 14.5, H-4), 3.15 (s, 3 H, OCH3), 7.30 (br
s, 1 H, OH), 9.20 (br s, 1 H, NH)d
2cc
1.13 (d, 3 H, 3JH–H4 = 7.2, CH3), 1.14 (t, 3 H, 3JH–H = 7.0,
CH3), 2.26 (dq, 1 H, 3JH4–H3 = 8.6, 3JH4–CH3 = 7.2, H-4),
3.55–3.65 (m, 2 H, OCH2), 3.79 (d, 1 H, 3JH3–H4 = 8.6, H-
3), 7.75 (s, 1 H, OH), 9.20 (br s, 1 H, NH)
2c
0.95 (d, 3 H, 3JH–H4 = 7.2, CH3), 1.14 (t, 3 H, 3JH–H = 7.0,
CH3), 2.74 (quin, 1 H, 3JH4–H3 = 7.2, 3JH4–CH3 = 7.2, H-4),
3.55–3.65 (m, 2 H, OCH2), 3.92 (d, 1 H, 3JH3–H4 = 7.2, H-
3), 8.11 (s, 1 H, OH), 9.08 (br s, 1 H, NH)
3-Alkoxy-5-hydroxy-5-trifluoromethylpyrrolidin-2-ones (2a–
h); General Procedure
2dc
2eb
2e
1.80–1.90 (m, 1 H, CH2), 2.25–2.30 (m, 1 H, CH2), 3.00
To a solution of ketones 1a–h (5 mmol) in MeOH or EtOH (3 mL),
a solution of NaCN (5 mmol, 0.25 g in 3 mL of H2O) was added at
r.t. under magnetic stirring, from 4 to 48 h (see Table 1). After half
of the reaction time, another equiv of sodium cyanide solution (5
mmol, 0.25 g in 3 mL of H2O) was added. A second addition of
NaCN improved the yields of 10–25%. The reaction was extracted
with CH2Cl2 (3 20 mL), washed with distilled H2O (1 20 mL),
and the organic layer was dried (MgSO4). Evaporation of the sol-
vent under vacuum resulted in light yellow oils for 2a–d and white
solids for 2e–h. The oils were analyzed without further purification
since tentative purification using column chromatography (30 g of
silica gel 60 for 0.5 g of the product) were unsuccessful. The solid
products 2e–h were recrystallized from MeOH in CHCl3 (10%).
Yields and selected physical and spectroscopic data are presented in
Table 1. 1H and 13C NMR data are presented in Table 2 and Table 3,
respectively.
(m, 1 H, H-4), 3.54 (ddd, 1 H, 2JOCH2 = 15.6, 3JOCH2–CH2
=
8.2, 3JOCH2–CH2,e OCH2), 3.82 (m, 1 H, OCH2), 4.42 (d, 1 H,
3JH3–H4 = 7.8, H-3), 6.08 (br s, 2 H, OH, NH)
1.64–1.88 (m, 2 H, CH2), 1.88–2.27 (m, 2 H, CH2), 2.20–
2.27 (m, 1 H, H-4), 3.36–3.86 (m, 2 H, OCH2), 4.15 (d, 1
H, 3JH3–H4 = 9.7, H-3), 7.28 (s, 1 H, OH), 9.24 (br s, 1 H,
NH)
1.64–1.88 (m, 2 H, CH2), 1.88–2.27 (m, 2 H, CH2), 2.33–
2.42 (m, 1 H, H-4), 3.36–3.86 (m, 2 H, OCH2), 4.00 (d, 1
H, 3JH3–H4 = 9.7, H-3), 7.60 (s, 1 H, OH), 9.11 (br s, 1 H,
NH)
2fb
2f
2.52–2.78 (m, 2 H, H-4), 3.32 (OCH3), 7.03–7.93 (Ph)f
2.52–2.78 (m, 2 H, H-4), 3.25 (OCH3), 7.03–7.93 (Ph)f
2gc
2.36 (CH3), 2.55–2.75 (m, 2 H, H-4), 3.24 (OCH3), 6.99–
7.80 (4-CH3Ph), 7.00 (s, 1 H, OH), 8.76 (br s, 1 H, NH)
Acknowledgment
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), PADCT-III/CNPq 62.0228/97-0
– QEQ, and Fundação de Apoio a Pesquisa do Estado do Rio Gran-
de do Sul (FAPERGS) for financial support. Fellowships from
CAPES (L. S. R. and M. F. M. C.) and CNPq (S. B.) are also ack-
nowledged.
2g
2.34 (CH3), 2.55–2.75 (m, 2 H, H-4), 3.30 (OCH3), 6.99–
7.80 (4-CH3Ph), 7.50 (s, 1 H, OH), 8.90 (br s, 1 H, NH)
2hb
2h
2.53–2.73 (m, 1 H, H-4), 3.22 (OCH3), 6.89–7.96 (4-FPh)f
2.53–2.73 (m, 2 H, H-4), 3.18 (OCH3), 6.89–7.96 (4-FPh)f
a The minor isomer of each compound was designated with a prime.
Compounds 2a,c–f,h were registered at 400 MHz and 2b,g were reg-
istered at 200 MHz.
References
b Spectrum registered in CDCl3–TMS.
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(3) Zhu, S.; Qin, C.; Xu, G.; Chu, Q.; Huang, Q. J. Fluorine
Chem. 1999, 99, 141.
c Spectrum registered in DMSO-d6–TMS.
d H-4 and H-4 may be interconverted.
e Coupling constant could not be measured.
f Signal of OH and NH superimposed with the aromatic hydrogens.
Synthesis 2002, No. 16, 2404–2408 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
One Pot Synthesis of 3-Alkoxy-5-hydroxy-5-trifluoromethylpyrrolidin-2-ones
2407
Table 3 13C NMR Spectral Data of Compounds 2a–h
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Com-
pound
13C NMR, , JCF (Hz)a
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2ab
14.87 (CH3), 37.80 (C-4), 67.04 (OCH2), 75.20 (C-3),
84.31 (q, 2JCF = 34, C-5), 123.38 (q, 1JCF = 284, CF3),
175.39 (C-2)
2a
14.72 (CH3), 36.30 (C-4), 66.35 (OCH2), 74.34 (C-3),
84.22 (q, 2JCF = 34, C-5), 123.78 (q, 1JCF = 285, CF3),
176.82 (C-2)
2bc
2b
22.80 (CH3), 40.50 (C-4), 51.29 (OCH3), 78.50 (C-3),
82.63 (q, 2JCF = 32, C-5), 124.22 (q, 1JCF = 285, CF3),
175.09 (C-2)
23.40 (CH3), 39.65 (C-4), 50.90 (OCH3), 78.09 (C-3),
82.54 (q, 2JCF = 33, C-5), 122.95 (q, 1JCF = 285, CF3),
175.86 (C-2)
2cc
2c
11.72 (CH3), 15.28 (CH3), 40.52 (C-4), 67.21 (OCH2),
80.73 (C-3), 92.50 (q, 2JCF = 32, C-5), 122.84 (q,
1JCF = 290, CF3), 174.66 (C-2)
8.14 (CH3), 15.07 (CH3), 38.38 (C-4), 67.65 (OCH2),
77.55 (C-3), 83.45 (q, 2JCF = 31, C-5), 123.66 (q,
1JCF = 285, CF3), 173.60 (C-2)
2dc
2eb
2e
26.80 (CH2), 42.91 (C-4), 68.03 (OCH2), 79.98 (C-3),
84.58 (q, 2JCF = 32, C-5), 124.32 (q, 1JCF = 287, CF3),
173.09 (C-2)
21.97 (CH2), 24.77 (CH2), 36.56 (C-4), 63.77 (OCH2),
75.89 (C-3), 85.24 (q, 2JCF = 32, C-5), 124.45 (q,
1JCF = 287, CF3), 172.69 (C-2)
(21) Bertele, E.; Boss, H.; Dunitz, J. D.; Elsinger, F.;
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Meyer, E. F.; Pesaro, M.; Scheffold, R. Angew. Chem., Int.
Ed. Engl. 1964, 76, 393.
19.70 (CH2), 25.72 (CH2), 44.72 (C-4), 68.77 (OCH2),
72.83 (C-3), 83.06 (q, 2JCF = 32, C-5), 123.48 (q,
1JCF = 285, CF3), 172.47 (C-2)
2f b
2f
43.81 (C-4), 52.33 (OCH3), 82.13 (C-3), 84.47 (q,
2JCF = 33, C-5), 123.42 (q, 1JCF = 286, CF3), 126–130 (Ph),
170.53 (C-2)
(22) Cheng, X. M. In Annual Reports in Medicinal Chemistry,
Vol. 29; Bristol, J. A., Ed.; Academic Press: New York,
1994, 43.
(23) Lui, N.; Baasner, B. Ger. Offen. DE 4 441 984, 1996; Chem.
Abstr. 1996, 125, 114474n.
(24) Lui, N.; Negele, M.; Baasner, B.; Jonge, M.; Schuurman, T.
Ger. Offen. DE 4 433 266, 1996; Chem. Abstr. 1996, 124,
343105q.
(25) Colla, A.; Clar, G.; Martins, M. A. P.; Krimmer, S.; Fischer,
P. Synthesis 1991, 483.
(26) Martins, M. A. P.; Zoch, A. N.; Flores, A. F. C.; Clar, G.;
Zanatta, N.; Bonacorso, H. G. J. Heterocycl. Chem. 1995,
32, 739.
(27) Martins, M. A. P.; Siqueira, G.; Bastos, G. P.; Zanatta, N. J.
Heterocycl. Chem. 1996, 33, 1223.
40.80 (C-4), 51.58 (OCH3), 79.12 (C-3), 83.02 (q,
2JCF = 33, C-5), 123.90 (q, 1JCF = 286, CF3), 126–130 (Ph),
173.33 (C-2)
2gc
2g
20.58 (CH3), 44.12 (C-4), 52.13 (OCH3), 81.53 (C-3),
83.95 (q, 2JCF = 33, C-5), 119.83 (q, 1JCF = 285, CF3),
125.50–138.82 (PhCH3), 170.43 (C-2)
20.29 (CH3), 44.12 (C-4), 51.40 (OCH3), 81.53 (C-3),
82.39 (q, 2JCF = 33, C-5), 119.83 (q, 1JCF = 285, CF3),
125.50–138.82 (PhCH3), 173.32 (C-2)
2hb
2h
44.72 (C-4), 52.93 (OCH3), 81.77 (C-3), 83.02 (q,
2JCF = 33, C-5), 123.43 (q, 1JCF = 285, CF3), 114.84–
134.34 (PhF), 162.22 (d, 1JCF = 247, CF), 173.56 (C-2).
(28) Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta, N.
J. Heterocycl. Chem. 1996, 33, 1619.
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A.; Bonacorso, H. G.; Zanatta, N. Tetrahedron Lett. 2000,
41, 293.
41.19 (C-4), 52.09 (OCH3), 81.77 (C-3), 83.02 (q,
2JCF = 33, C-5), 123.43 (q, 1JCF = 285, CF3), 114.84–
134.34 (PhF), 162.22 (d, 1JCF = 247, CF), 173.56 (C-2)
(30) Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta, N.
J. Heterocycl. Chem. 1995, 32, 1491.
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B.; Hörner, M.; Zanatta, N.; Martins, M. A. P. Tetrahedron
1999, 55, 345.
(32) Pacholski, I. L.; Blanco, I.; Zanatta, N.; Martins, M. A. P. J.
Braz. Chem. Soc. 1992, 2, 118.
a The minor isomer of each compound was designated with a prime.
Compounds 2a,c–f,h were registered at 100 MHz and 2b,g were reg-
istered at 50 MHz.
b Spectrum registered in CDCl3/TMS.
c Spectrum registered in DMSO-d6/TMS.
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(33) Zanatta, N.; Madruga, C. C.; Marisco, P. C.; Flores, D. C.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem.
2000, 37, 1213.
(38) Bonacorso, H. G.; Bittencourt, S. R. T.; Wastowski, A. D.;
Wentz, A. P.; Zanatta, N.; Martins, M. A. P. J. Heterocycl.
Chem. 1999, 36, 45.
(34) Zanatta, N.; Madruga, C. C.; Clerice, E.; Martins, M. A. P.
J. Heterocycl. Chem. 1995, 32, 735.
(39) Zanatta, N.; Barichello, R.; Bonacorso, H. G.; Martins, M.
A. P. Synthesis 1999, 765.
(35) Zanatta, N.; Cortelini, M. F.; Carpes, M. J. S.; Bonacorso, H.
G.; Martins, M. A. P. J. Heterocycl. Chem. 1997, 34, 509.
(36) Zanatta, N.; Fagundes, M. B.; Hellensohn, R.; Martins, M.
A. P.; Bonacorso, H. G. J. Heterocycl. Chem. 1998, 35, 451.
(37) Bonacorso, H. G.; Bittencourt, S. R. T.; Wastowski, A. D.;
Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Tetrahedron
Lett. 1996, 37, 9155.
(40) Lee, H.-S.; Kim, K. Tetrahedron Lett. 1998, 39, 6895.
(41) Sanders, J. K. M.; Hunter, B. K. Modern NMR
Spectroscopy: A Guide for Chemists, 2nd ed.; Oxford: New
York, 1994, 97–153.
(42) Martins, M. A. P.; Siqueira, G. M.; Flores, A. F. C.; Clar, G.;
Zanatta, N. Química Nova 1994, 17, 24.
Synthesis 2002, No. 16, 2404–2408 ISSN 0039-7881 © Thieme Stuttgart · New York