Regioselective synthesis of 6-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[3,4-b]pyran derivatives

Article abstract of DOI:10.1016/j.jfluchem.2007.04.004

A facile two-step procedure for the synthesis of 6-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-b]pyran derivatives (4) from the reaction of 4-arylidene-3-methyl-1-phenyl-5-pyrazolones (1) with ethyl trifluoroacetoacetate (2), a versatile fluorinated

Full text of DOI:10.1016/j.jfluchem.2007.04.004

Journal of Fluorine Chemistry 128 (2007) 952–957
www.elsevier.com/locate/fluor
Regioselective synthesis of
6-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[3,4-b]pyran derivatives
a
b,
Dongmei Li a, Liping Song a,b, , Shaodi Song , Shizheng Zhu
*
*
a Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 12 January 2007; received in revised form 4 April 2007; accepted 4 April 2007
Available online 8 April 2007
Abstract
A facile two-step procedure for the synthesis of 6-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-b]pyran derivatives (4) from the reaction of
4-arylidene-3-methyl-1-phenyl-5-pyrazolones (1) with ethyl trifluoroacetoacetate (2), a versatile fluorinated building-block, was presented.
Furthermore, to increase the efficiency of this reaction, the more convenient one-pot three-component process was also developed with a slightly
lower yield. Treatment of 4 with P2O5, conc. H2SO4, POCl3/Py or p-TsOH under the drastic conditions did not afford the corresponding dehydrated
products.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Ammonium acetate; Ethyl trifluoroacetoacetate; 4-Arylidene-3-methyl-1-phenyl-5-pyrazolones; 3-Methyl-1-phenyl-5-pyrazolone
1. Introduction
have previously reported the synthesis of 2-trifluoromethyl-3,4-
dihydro-2H-pyran derivatives by the reaction of ethyl
trifluoroacetoacetate with arylidenemalononitrile (Scheme 1)
[13].
The introduction of a trifluoromethyl group into an organic
compound can bring about remarkable changes in the physical,
chemical and biological properties [1–3]. Thus, trifluoro-
methyl-substituted compounds are becoming increasingly
important for the development of new agrochemicals and
medicines. In recent years, the synthesis of fluorinated O-
heterocyclic or N-heterocyclic compounds have draw much
attention [4–6]. The b-ketoesters are well established as
synthetic intermediates in heterocyclic chemistry [7]. The
literature has reported a series of CF3-substituted pyridines,
pyrazoles and pyrans and their derivatives, which were
prepared from the reactions of trifluoromethyl-1, 3-dicarbonyl
compounds as fluorine-containing building-blocks [8–10]. For
example, our group have reported the synthesis of a series of
trifluoromethyl-containing pyrazole derivatives [9,11].
Owning to numerous advantages associated with ethyl
trifluoroacetoacetate as fluorinated building-block and in
continuation of our work, we focused our attention on the
reaction of ethyl trifluoroacetoacetate with another a,b-
unsaturated carbonyl compounds. In this paper, we wish to
report the preparation of 6-(trifluoromethyl)-1,4,5,6-tetrahy-
dropyrazolo[3,4-b]pyran derivatives (4) in the presence of
ammonium acetate in good to excellent yields.
2. Results and discussion
Initially, we tried the reaction of ethyl trifluoroacetoacetate
(2) with 4-benzylidene-3-methyl-1-phenyl-5-pyrazolones (1a),
obtained from the condensation of benzaldehyde with 3-
methyl-1-phenyl-5-pyrazolone, in the presence of triethyla-
mine (0.5 equiv.) in ethanol. The reaction was carried out under
the different conditions such as by varying the reaction
temperature from room temperature to refluxing, however, the
major product was not obtained. Then, we investigated the
reaction using secondary amine, piperidine (0.5 equiv.) and a
Evans and co-workers have reported the preparation of
2H,4H-dihydropyrazolo[3,4-b]pyrans from the reaction of
4-piperidines, 5-pyrazolones and malononitrile [12]. And we
* Corresponding authors.
E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.04.004

D. Li et al. / Journal of Fluorine Chemistry 128 (2007) 952–957
953
Scheme 1.
Scheme 2.
major solid product was isolated by chromatography column in
low yield (34%). To our surprise, the 19F NMR spectra clearly
showed that no fluorine atom attached to the solid product. On
the basis of 1H NMR spectra data and IR analysis, the product
was identified as 5,50-dimethyl-2,20-diphenyl-1,2,10,20-tetrahy-
dro-4,40-phenylmethanediyl-bis-pyrazol-3-one (3), other than
the expected fluorinated products (Scheme 2). The obtained
product (3) was the same as the previous reported product [14],
despite the different starting materials were applied to the
reaction (Scheme 2). The result revealed that, to some extent,
the basicity of piperidine was too strong to be involved in the
reaction, leading to the cleavage of carbon–carbon double
bond, in other words, the occurrence of retro-knoevenagel
condensation of 4-arylidene-3-methyl-1-phenyl-5-pyrazolone
in the presence of a trace amount of water. Subsequently, the
newly generated 3-methyl-1-phenyl-5-pyrazolone reacted with
the substrate 1a to afford the 3.
2H, CH2), 3.11 (d, J = 11.1 Hz, 1H, CH), 1.64 (s, 3H, CH3),
0.96 (t, J = 7.2 Hz, 3H, CH3), which were corresponding to 10
aromatic protons, 1 hydroxy proton, 2 six-membered ring
protons, 1 ethoxy group (CH3CH2O) and 1 methyl group. The
structure of 4a is clearly assigned as trans by the analysis of the
vicinal coupling constant of the two methine protons
(J = 11.7 Hz) and by the analogy with earlier reported paper
[20,21]. In its 19F NMR spectrum, the chemical shift of CF3
group of 4a was a singlet peak at d ꢀ83.60 ppm, which
indicated it was bonded the sp3 saturated carbon atom. The MS
spectrum of 4a showed a weak molecular ion peak at m/z 447
(M+, 1.68%), and the base peak as well as the rest of strong
+
peaks was at m/z 77 (C6H5 , 100%), 261 ([M-1-CF3COCH2-
+
CO2Et]+, 91.25%), 69 (CF3 , 56.97%), respectively. Mean-
while, the typical and strong absorption at 3537 cmꢀ1 in IR
spectrum also confirmed the existence of OH group in 4a.
4-Arylidene-3-methyl-1-phenyl-5-pyrazolones (1b–i) bear-
ing a variety of functional groups also gave the corresponding
pyran derivatives 4 in good to excellent yields (Scheme 3;
Table 1). It should be noted that, in some cases, the products
were complexed with one molecular ethanol or water, based on
the evidence revealed by 1H NMR and microanalysis (Scheme
4; Fig. 1).
More recently, ammonium acetate has been used widely as a
base or a catalyst in Biginelli reactions [15,16], Hantsch
reactions [17] and other reactions [18,19]. With this aim in
view, we applied the ammonium acetate to this reaction.
Treatment of 3-methyl-1-phenyl-4-phenylidene-5-pyrazolone
(1a) with 1 equiv. of ammonium acetate followed by 2 in
ethanol at room temperature for 2 h gave the corresponding
1,4,5,6-tetrahydropyrazolo[3,4-b]pyran 4a exclusively in 70%
yield. Spectroscopic analysis supported the structure assign-
Furthermore, in attempt to enhance the efficiency of this
reaction, we investigated the development of a stoichiometric
one-pot three-component process, in which the enone 1 could
be generated in situ from the corresponding aldehydes and 3-
methyl-1-phenyl-5-pyrazolone (Scheme 5). To the ethanol
solution of 3-methyl-1-phenyl-5-pyrazolone was added
1
ment. For instance, the H NMR spectrum of 4a in CDCl3
consisted of eight peaks: 7.73–7.23 (m, 10H, ArH), 5.93 (s, 1H,
OH), 4.25 (d, J = 11.1 Hz, 1H, CH), 4.06–3.98 (q, J = 7.2 Hz,
Scheme 3.

954
D. Li et al. / Journal of Fluorine Chemistry 128 (2007) 952–957
Table 1
benzaldehyde followed by 2 and ammonium acetate, the
resultant mixture was stirred at room temperature for 2 h,
general workup afforded 4a in 60% yield (Table 2).
Synthesis of 6-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-b]pyran deri-
vativesa
Entry
1 R
Reaction time (h)
Product yieldb (%)
However, our attempts to prepare the dehydrated product
according to the procedure for the synthesis of trifluoromethyl-
substituted pyrazole derivatives failed [9], demonstrating an
unusual stability of this fused heterocyclics. Compared with the
a-hydroxytetrahydropyridine, which smoothly eliminated water
to form the corresponding 1,4-dihydropyridines [22a,22b], the
product 4 was unaffected by either conc. H2SO4, P2O5 in CHCl3
or POCl3/Py, p-TsOH in boiling toluene. The result was
consistent with Martins’ reported work that the dehydration
reaction was an elimination reaction where the stability of its
activated complex depended on the participation of electron pair
of neighbor heteroatom present in the heterocyclic ring. The
more difficult dehydration of compounds 4 compared to a-
hydroxytetrahydropyridine was caused by the weaker electron-
donating strength of the oxygen atom in the pyran ring than that
of the nitrogen atom in the pyridine ring [22c].
1
2
1a C6H5
2
2
4
1
1
1
1
1
2
4
8
70
88
1b p-CH3C4H6
1c p-CH3OC4H6
1d p-NO2C6H4
1e p-BrC6H4
1f o-BrC6H4
1g o-FC6H4
1h m-ClC6H4
1i o-HOC6H4
1j furan-2-yl
1k iso-C3H7
3
60
4
91
5
90
6
65
7
81
8
79
9
100
b
10
11
–
b
–
In order to definitely determine the structure of this series of compound, 4c was
further confirmed by the single crystal X-ray crystallographic study. The
molecular structure of 4c is shown in Fig. 1. Some selected bond lengths
and angles are listed in Table 2.
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), ammonium acetate (1 mmol)
and ethanol (5 mL) as solvent at room temperature;.
b
No reaction occurred.
In conclusion, we have developed a convenient reaction for
the synthesis of compounds (4a–i) from readily available starting
ethyl trifluoroacetoacetate and enones with a variety of
functional groups under the mild reaction condition. To increase
the efficiency of this reaction, the one-pot three-component
Scheme 4.
Fig. 1. (a) Crystal structure of compound 4c and (b) packing map of molecular 4c on the basis of this finding, a plausible reaction mechanism is shown in Scheme 4.

D. Li et al. / Journal of Fluorine Chemistry 128 (2007) 952–957
955
Scheme 5.
Table 2
ethyl acetate (3 ꢁ 20 mL), washed with H2O, dried (Na2SO4)
and concentrated in vacuo. The residue was chromatographed
over silica gel, eluted with hexane/ethyl acetate (5/1) to give 4a
as a sole product.
Selected bond length and bond angle of compound 4c
˚
Bond length (A)
Bond angle (8)
C(4)–C(8)
1.515 (5)
1.502 (5)
1.546 (5)
1.360 (5)
1.401 (5)
1.360 (4)
1.362 (4)
1.448 (4)
1.529 (5)
1.540 (5)
O(3)–C(11)–C(24)
O(2)–C(11)–C(12)
C(10)–C(9)–C(13)
C(9)–C(10)–N(2)
C(4)–C(8)–C(12)
C(9)–C(8)–C(4)
105.8 (3)
109.6 (3)
103.9 (3)
110.3 (3)
111.8 (3)
113.8 (3)
112.8 (3)
109.4 (3)
113.1 (2)
131.9 (3)
C(8)–C(9)
C(8)–C(12)
C(9)–C(10)
C(9)–C(13)
C(10)–O(2)
C(10)–N(2)
C(11)–O(2)
C(11)–C(24)
C(11)–C(12)
3.2. One-pot reaction
A mixture of ethyl trifluoroacetoacetate (2; 184 mg,
1 mmol), benzaldehyde (106 mg, 1 mmol), 3-methyl-1-phe-
nyl-5-pyrazolone (174 mg, 1 mmol) and ammonium acetate
(77 mg, 1 mmol) in ethanol (5 mL) was stirred at room
temperature for 2 h. The reaction mixture was diluted with
ethyl acetate (3 ꢁ 20 mL), washed with H2O, dried (Na2SO4)
and concentrated in vacuo. The residue was chromatographed
over silica gel, eluted with hexane/ethyl acetate (5/1) to give 4a
as a sole product.
C(21)–C(12)–C(11)
C(11)–C(12)–C(8)
C(10)–O(2)–C(11)
C(10)–N(2)–C(15)
process was also developed, in which the enone was generated in
situ from aldehyde and 3-methyl-1-phenyl-5-pyrazolone.
3. Experimental
3.2.1. 1,4-Diphenyl-5-ethoxylcarbonyl-6-hydroxy-3-
methyl-6-(trifluoromethyl)-1,4,5,6 -tetrahydropyrazolo[3,4-
b]pyran (4a)
Melting points were measured in Melt-Temp apparatus and
1
were uncorrected. H and 19F NMR spectra were recorded in
White solid; mp: 88–90 8C; FT-IR ymax (KBr, cmꢀ1): 3537,
2982, 2937, 1745, 1601, 1522, 1497, 1194, 1010, 754, 703; 1H
NMR d (CDCl3): 7.73–7.23 (m, 10H, ArH), 5.93 (s, 1 H, OH),
4.25 (d, J = 11.1 Hz, 1 H, CH), 4.06–3.98 (q, J = 7.2 Hz, 2H,
CH2), 3.11 (d, J = 11.1 Hz, 1H, CH), 1.64 (s, 3H, CH3), 0.96 (t,
J = 7.2 Hz, 3H, CH3) ppm; 19F NMR (CDCl3, 282 MHz) d:
ꢀ83.60 (s, 3F, CF3) ppm; MS (70 eV, EI) m/z (%): 447 ([M+1]+,
CDCl3 on a Bruker AM-300 instruments with Me4Si and CFCl3
(with upfield negative) as the internal and external standards,
respectively. IR spectra were obtained with a Nicolet AV-360
spectrophotometer. Low resolution mass spectrum was
obtained using the either electron impact ionization technique
(70 eV) or electro-spray ionization mass spectra (ESIMS),
respectively. Elemental analyses were performed by this
Institute. X-ray diffraction crystal structure analysis was
obtained on a Bruker P4 instrument. Compounds 1a–i were
prepared according to the literature methods [23].
+
1.68), 261 ([M-1-CF3COCH2CO2Et]+, 91.24), 77 (C6H5 , 100),
+
69 (CF3 , 56.97); anal. calcd. for C23H21F3N2O4ꢂH2O: C,
59.48; H, 4.96; N, 6.03; found: C, 59.48; H, 4.97; N, 5.88%.
The crystal data of 4c: C24H23F3N2O5, FW = 476.44,
temperature 273(2)(K), monoclinic, P2(1)/c, wavelength
3.2.2. 5-Ethoxylcarbonyl-6-hydroxy-3-methyl-1-phenyl-4-
tolyl-6-(trifluoromethyl)-1,4,5, 6-tetrahydropyrazolo[3,4-
b]pyran (4b)
˚
˚
˚
0.71073 A, a = 13.443(5) A, a = 908, b = 10.169(4) A, b =
3
94.817(5)8, c = 16.940(7) A, g = 908, V = 2307.5(16) A ,
Z = 4, Dc = 1.371 mg/m3, absorption coefficient 0.112 mmꢀ1
F(0 0 0) = 992, 2.38 < u < 25.008, reflections collected 11,322,
White solid; mp: 100–102 8C; FT-IR ymax (KBr, cmꢀ1):
3755, 2982, 2927, 1746, 1601, 1518, 1497, 1196, 1009, 756,
691; 1H NMR d (CDCl3): 7.75–7.13 (m, 9H, ArH), 5.68 (s, 1H,
OH), 4.22 (d, J = 11.1 Hz, 1H, CH), 4.06–4.03 (q, J = 7.2 Hz,
2H, CH2), 3.14 (d, J = 11.1 Hz, 1H, CH), 1.68 (s, 3H, CH3),
0.99 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR (CDCl3,
282 MHz) d: –83.69 (s, 3F) ppm; MS (ESI): 461 (M++H);
anal. calcd. for C24H23F3N2O4: C, 62.61; H, 5.00; N, 6.09;
found: C, 62.67; H, 5.07; N, 5.95%.
˚
˚
,
absorption correction expirical, transmission 0.9672max
0.9565min, final R indices R1 = 0.0787, wR2 = 0.2122.
ꢀ
3.1. Reactions between enones (1) and ethyl
trifluoroacetoacetate (2) to produce 6-(trifluoromethyl)-
1,4,5,6-tetrahydropyrazolo[3,4-b]pyrans (4) typical
procedure
3.2.3. 5-Ethoxylcarbonyl-6-hydroxy-3-methyl-4-(4-
methoxylphenyl)-1-phenyl-6-(trifluoro methyl)-1,4,5,6-
tetrahydropyrazolo[3,4-b]pyran (4c)
White solid; mp: 93–96 8C; FT-IR ymax (KBr, cmꢀ1): 3753,
2982, 2929, 1744, 1686, 1601, 1514, 1459, 1341, 1250, 1188,
A mixture of enone (1a; 264 mg, 1 mmol), ethyl trifluor-
oacetoacetate (2; 184 mg, 1 mmol) and ammonium acetate
(77 mg, 1 mmol) in ethanol (5 mL) was stirred at room
temperature for 2 h. The reaction mixture was diluted with

956
D. Li et al. / Journal of Fluorine Chemistry 128 (2007) 952–957
756, 692; 1H NMR d (CDCl3): 7.73–6.86 (m, 9H, ArH), 5.78 (s,
1H, OH), 4.21 (d, J = 11.4 Hz, 1H, CH), 4.08–4.01 (q,
J = 7.2 Hz, 2H, CH2), 3.82 (S, 3H, OCH3), 3.07 (d,
J = 11.4 Hz, 1H, CH), 1.67 (s, 3H, CH3), 1.00 (t, J = 7.2 Hz,
3H, CH3) ppm; 19F NMR (CDCl3, 282 MHz) d: ꢀ83.67 (s, 3F)
ppm; MS (ESI): 477 (M++H); anal. calcd. for C24H23F3N2O5:
C, 60.50; H, 4.83; N, 5.88; found: C, 60.51; H, 4.88; N, 5.73%.
691; 1H NMR d (CDCl3): 7.79–7.06 (m, 9H, ArH), 6.01 (s, 1H,
OH), 4.68 (d, J = 11.7 Hz, 1H, CH), 4.13–4.02 (q, J = 7.2 Hz,
2H, CH2), 3.23 (d, J = 11.7 Hz, 1H, CH), 1.65 (s, 3H, CH3),
1.00 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR (CDCl3,
282 MHz) d: ꢀ83.62 (s, 3F, CF3), ꢀ119.61 (s, 1F, ArF)
ppm; MS (ESI): 465 (M++H); anal. calcd. for
C23H20F4N2O4ꢂH2O: C, 57.26; H, 4.56; N, 5.81; found: C,
57.38; H, 4.51; N, 5.56%.
3.2.4. 5-Ethoxylcarbonyl-6-hydroxy-3-methyl-4-(4-
nitrophenyl)-1-phenyl-6-(trifluorome-thyl)-1,4,5,6-
3.2.8. 4-(2-Chlorophenyl) 5-ethoxylcarbonyl-6-hydroxy-3-
methyl-1-phenyl-6-(trifluoro-methyl)-1,4,5,6-
tetrahydropyrazolo[3,4-b]pyran (4d)
White solid; mp: 99–101 8C; FT-IR ymax (KBr, cmꢀ1): 3753,
2372, 2346, 1743, 1599, 1523, 1348, 1194, 1009, 758, 693; 1H
NMR d (CDCl3): 8.25–7.26 (m, 9H, ArH), 6.08 (s, 1H, OH),
4.42 (d, J = 11.1 Hz, 1H, CH), 4.09–4.01 (q, J = 7.2 Hz, 2H,
CH2), 3.74–3.67 (q, J = 7.2 Hz, 2H, CH3CH2OH), 3.08 (d,
J = 11.1 Hz, 1H, CH), 1.62 (s, 3H, CH3), 1.22 (t, J = 7.2 Hz,
3H, CH3CH2OH), 1.01 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR
(CDCl3, 282 MHz) d: –83.32 (s, 3F, CF3) ppm; MS (ESI): 492
(M+); anal. calcd. for C23H20F3N3O6ꢂCH3CH2OH: C, 55.66; H,
4.82; N, 7.79; found: C, 55.89; H, 4.85; N, 7.73%.
tetrahydropyrazolo[3,4-b]pyran (4h)
White solid; mp: 91–92 8C; FT-IR ymax (KBr, cmꢀ1): 3336,
3066, 2983, 1744, 1715, 1599, 1522, 1498, 1195, 1164, 1076,
1009, 757, 691; 1H NMR d (CDCl3): 7.78–7.12 (m, 9H, ArH),
5.96 (s, 1H, OH), 4.23 (d, J = 11.7 Hz, 1H, CH), 4.10–4.03 (q,
J = 7.2 Hz, 2H, CH2), 3.06 (d, J = 11.7 Hz, 1H, CH), 1.67 (s,
3H, CH3), 1.02 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR
(CDCl3, 282 MHz) d: ꢀ83.51 (s, 3F, CF3) ppm; MS (ESI): 481
(M++H); anal. calcd. for C23H20ClF3N2O4ꢂH2O: C, 55.37; H,
4.41; N, 5.62; found: C, 55.22; H, 4.62; N, 5.54%.
3.2.5. 4-(4-Bromophenyl)-5-ethoxylcarbonyl-6-hydroxy-3-
methyl-1-phenyl-6-(trifluorom-ethyl)-1,4,5,6-
3.2.9. 5-Ethoxylcarbonyl-6-hydroxy-4-(2-hydroxylphenyl)-
3-methyl-1-phenyl-6-(trifluo-romethyl)-1,4,5,6-
tetrahydropyrazolo[3,4-b]pyran (4e)
tetrahydropyrazolo[3,4-b]pyran (4i)
White solid; mp: 105–109 8C; FT-IR ymax (KBr, cmꢀ1):
3651, 2982, 2374, 1745, 1702, 1601, 1522, 1235, 1199, 1072,
1011, 757, 692; 1H NMR d (CDCl3): 7.73–7.13 (m, 9H, ArH),
5.63 (s, 1H, OH), 4.24 (d, J = 10.2 Hz, 1H, CH), 4.08–4.04 (q,
J = 7.2 Hz, 2H, CH2), 3.06 (d, J = 10.2 Hz, 1H, CH), 1.68 (s,
3H, CH3), 1.03 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR
(CDCl3, 282 MHz) d: ꢀ83.60 (s, 3F, CF3) ppm; MS (ESI): 525
(M+); anal. calcd. for C23H20BrF3N2O4: C, 52.57; H, 3.81; N,
5.33; found: C, 52.54; H, 3.86; N, 5.06%.
White solid; mp: 136–138 8C; FT-IR ymax (KBr, cmꢀ1):
3426, 2974, 2362, 2334, 1716, 1622, 1583, 1487, 1231, 1186,
1088, 1023, 990, 758; 1H NMR d (CDCl3): 7.47–6.91 (m, 9H,
ArH), 5.38 (s, 1H, OH), 4.39 (d, J = 11.7 Hz, 1H, CH), 4.15–
4.12 (q, J = 7.2 Hz, 2H, CH2), 3.07 (d, J = 11.7 Hz, 1H, CH),
1.62 (s, 3H, CH3), 1.05 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR
(CDCl3, 282 MHz) d: ꢀ84.16 (s, 3F, CF3) ppm; MS (70eV, EI)
m/z (%): 462 (M+, 3.09), 371 ([M-C7H7]+, 4.52), 278 ([M-
CF3COCH2CO2Et]+, 100), 277 ([M-1-CF3COCH2CO2Et]+,
+
+
51.03), 77 (C6H5 , 24.78), 69 (CF3 , 24.66); anal. calcd. for
C23H21F3N2O5: C, 59.74; H, 4.55; N, 6.06; found: C, 59.71; H,
4.56; N, 5.71%.
3.2.6. 4-(2-Bromophenyl)-5-ethoxylcarbonyl-6-hydroxy-3-
methyl-1-phenyl-6-(trifluorom-ethyl)-1,4,5,6-
tetrahydropyrazolo[3,4-b]pyran (4f)
White solid; mp: 101–103 8C; FT-IR ymax (KBr, cmꢀ1):
2988, 2965, 2358, 2339, 1749, 1601, 1532, 1499, 1211, 1172,
Acknowledgement
1
1018, 904, 755, 687; H NMR d (CDCl3): 7.74–7.18 (m, 9H,
This work is supported by the National Science Foundation
of China (Nos. 20672072, 20532040).
ArH), 6.14 (s, 1H, OH), 5.03 (d, J = 11.1 Hz, 1H, CH), 4.15–
4.08 (q, J = 7.2 Hz, 2H, CH2), 3.15 (d, J = 11.1Hz, 1H, CH),
1.64 (s, 3H, CH3), 1.01 (t, J = 7.2 Hz, 3H, CH3) ppm; 19F NMR
(CDCl3, 282 MHz) d: ꢀ83.59 (s, 3F, CF3) ppm; MS (70eV, EI)
m/z (%): 342/340 ([M-CF3COCH2CO2Et]+, 7.24/6.93), 262
References
[1] R.E. Bank, Organofluorine Chemistry: Principles and Commercial
Application, Plenum and Elsevier, New York, 1994.
([M-Br-CF3COCH2CO2Et]+,
20.41),
261
([M-1-Br-
CF3COCH2CO2Et]+, 100), 185 ([CF3COCH2CO2Et + 1]+,
[2] R.E. Filler, Organic Chemistry in Medicinal Chemistry and Biochemical
Applications, Plenum and Elsevier, Amsterdam, 1993.
+
8.44), 69 (CF3 , 59.46); anal. calcd. for C23H20BrF3N2O4ꢂH2O:
[3] R. Ling, M. Yoshida, P.S. Mariano, J. Org. Chem. 61 (1996) 4439–4449.
[4] I. Katsuyama, S. Ogawa, Y. Yamaguchi, K. Funabiki, M. Matsui, H.
Muramatsu, K. Shibata, Synthesis (1997) 1321–1324.
H2O: C, 50.83; H, 4.05; N, 5.16; found: C, 51.03; H, 3.89; N,
5.16%.
[5] H. Amii, T. Kobayashi, H. Terasawa, K. Uneyama, Org. Lett. 3 (2001)
3103–3105.
3.2.7. 5-Ethoxylcarbonyl-4-(2-fluorophenyl)-6-hydroxy-3-
methyl-1-phenyl-6-(trifluorom-ethyl)-1,4,5,6-
tetrahydropyrazolo[3,4-b]pyran (4g)
White solid; mp: 84–86 8C; FT-IR ymax (KBr, cmꢀ1): 3749,
2983, 1746, 1601, 1522, 1494, 1456, 1190, 1164, 1008, 756,
[6] C.H. Xing, S.Z. Zhu, J. Org. Chem. 69 (2004) 6486–6488.
[7] R.S. Atkinson, E. Barker, P.J. Edwards, G.A. Thomson, J. Chem. Soc.
Perkin Trans. 112 (1995) 1533–1543.
[8] A. Loupy, A. Petit, D.B. Delpon, J. Fluorine Chem. 75 (1995) 215–216.
[9] L.P. Song, S.Z. Zhu, J. Fluorine Chem. 111 (2001) 201–205.

D. Li et al. / Journal of Fluorine Chemistry 128 (2007) 952–957
957
[10] M. Marull, M. Schlosser, Eur. J. Org. Chem. 8 (2003) 1576–1588.
[11] L.P. Song, Q.L. Chu, S.Z. Zhu, J. Fluorine Chem. 107 (2001) 107–
112.
[19] R. Sakamoto, M. Ryoto, S. Kume, H. Sampei, M. Sugimoto, H. Nishihara,
Chem. Commun. 9 (2005) 1214–1217.
[20] C.P. Chuang, An-I. Tsai, Synthesis 4 (2006) 675–699.
[21] R. Antonioletti, S. Malancona, P. Bovicelli, Tetrahedron 58 (2002) 8825–
8831.
[12] A.M. Shestopalov, Y.M. Emeliyanova, A.A. Shestopalov, L.A. Rodinovs-
kaya, Z.I. Niazimbetova, D.G. Evans, Org. Lett. 4 (2002) 423–425.
[13] X.F. Li, L.P. Song, C.H. Xing, J.W. Zhao, S.Z. Zhu, Tetrahedron 62 (2006)
2255–2263.
[22] (a) I. Katsuyama, K. Funabiki, M. Matsui, H. Muramatsu, K. Shibata,
Tetrahedron Lett. 37 (24) (1996) 4177–4178;
[14] H.S. Ammida Nagwa, A. Giath, Asian J. Chem. 15 (2) (2003) 616–
620.
(b) V.G. Nenajdenko, S.V. Druzhinin, E.S. Balenkova, J. Fluorine Chem.
127 (2006) 865–873;
[15] J.S. Yadav, S.P. Kumar, G. Kondaji, R.S. Rao, K. Nagaiah, Chem. Lett. 33
(2004) 1168–1169.
(c) M.A.P. Martins, W. Cunico, S. Brondani, R.L. Peres, N. Zimmermann,
F.A. Rosa, G.F. Fiss, N. Zanatta, H.G. Bonacorso, Synthesis 9 (2006)
1485–1493.
[16] J. Mabry, B. Ganem, Tetrahedron Lett. 47 (2006) 55–56.
[17] J.H. Lee, Tetrahedron Lett. 46 (2005) 7329–7330.
[18] S. Mitsumori, H.L. Zhang, P.H. Cheong, K.N. Houk, F. Tanaka, C.F.
Barbas, J. Am. Chem. Soc. 128 (2006) 1040–1041.
[23] N.E. Seyhan, A.D. Adams, E.J. Gess, K.S. Ragone, B.J. Kober, M.B.
Lampert, P. Umrigar, D.C. Lankin, G.W. Griffin, J. Chem. Soc. Perkin
Trans. 1 (1983) 325–331.