Haloacetylated enol ethers 10. Condensation of β-alkoxyvinyl trifluoromethyl ketones with thiosemicarbazide. Synthesis of new trifluoromethyl 4,5-dihydro-1H-1-pyrazolethiocarboxyamides

Article abstract of DOI:10.1016/S0022-1139(98)00242-5

The synthesis of 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1- pyrazolethiocarboxyamides (2a-g) from the direct cyclo-condensation reaction of β-alkoxyvinyl trifluoromethyl ketones (1a-g) with thiosemicarbazide in methanol, under mild conditions, is reported. Similarly, the 1H-1-pyrazolethiocarboxyamide derivatives (2a-g) were easily dehydrated and the thiocarboxyamide group hydrolyzed in a one-step reaction by stirring with concentrated sulfuric acid to give the 3-aryl[alkyl]-5-trifluoromethyl-1H-pyrazoles (3a-g) in good yields. Specific syntheses and physical properties of 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1- pyrazolethiocarboxyamides are reported here for the first time.

Full text of DOI:10.1016/S0022-1139(98)00242-5

Journal of Fluorine Chemistry 92 (1998) 23±26
Haloacetylated enol ethers 10. Condensation of b-alkoxyvinyl
tri¯uoromethyl ketones with thiosemicarbazide. Synthesis of new
tri¯uoromethyl 4,5-dihydro-1H-1-pyrazolethiocarboxyamides
H.G. Bonacorso*, A.D. Wastowski, N. Zanatta, M.A.P. Martins, J.A. Naue
Â
Departamento de Quõmica, Universidade Federal de Santa Maria 97105-900, Santa Maria, RS, Brazil
Received 22 April 1998; accepted 26 June 1998
Abstract
The synthesis of 3-aryl[alkyl]-5-hydroxy-5-tri¯uoromethyl-4,5-dihydro-1H-1-pyrazolethiocarboxyamides (2a±g) from the direct cyclo-
condensation reaction of b-alkoxyvinyl tri¯uoromethyl ketones (1a±g) with thiosemicarbazide in methanol, under mild conditions, is
reported. Similarly, the 1H-1-pyrazolethiocarboxyamide derivatives (2a±g) were easily dehydrated and the thiocarboxyamide group
hydrolyzed in a one-step reaction by stirring with concentrated sulfuric acid to give the 3-aryl[alkyl]-5-tri¯uoromethyl-1H-pyrazoles (3a±g)
in good yields. Speci®c syntheses and physical properties of 3-aryl[alkyl]-5-hydroxy-5-tri¯uoromethyl-4,5-dihydro-1H-1-pyrazolethio-
carboxyamides are reported here for the ®rst time. # 1998 Elsevier Science S.A. All rights reserved.
Keywords: b-alkoxyvinyl tri¯uoromethyl ketones; 4,5-dihydro-1H-pyrazoles; Tri¯uoromethyl-1H-pyrazoles
1. Introduction
2. Results and discussion
Many tri¯uoromethylated 1H-pyrazoles and derivatives
are known to exhibit important biological activities in
medicinal and agricultural scienti®c ®elds [1±6]. Therefore,
much attention has been paid to the development of new
methods for the synthesis of ¯uorine containing hetero-
cycles. The synthesis of pyrazoles is relatively well explored
by the so-called [3‡2] atom fragments, where b-diketones
or derivatives thereof as the 3-atom fragment is condensed
with hydrazine or its derivatives (2-atom fragment) to close
the ®ve-membered ring [7]. In previous papers the versatility
of the b-alkoxyvinyl-b-aryl [alkyl] tri¯uoromethyl ketones
as readily available CCC building block for the regiospeci®c
construction of isoxazoles [8,9], pyrimidines [10,11], pyr-
azoles and pyrazolines [12], was reported.
With a continuing interest in heterocyclic structures that
may have biological activities, the aim of this work is to
report the results of the regiospeci®c synthesis of a series of
3-aryl[alkyl]-5-hydroxy-5-tri¯uoromethyl-4,5-dihydro-1H-
1-pyrazolethiocarboxyamides (2a±g) and 3-aryl[alkyl]-5-
tri¯uoromethyl-1H-pyrazoles (3a±g) from the reactions
of the 4-alkoxy-4-aryl[alkyl]-1,1,1-tri¯uoro-3-buten-2-ones
(1a±g) and thiosemicarbazide (Scheme 1).
The b-alkoxyvinyl tri¯uoromethyl ketones (1a±c) were
prepared according to Ref. [8] and the b-aryl-b-methoxy-
vinyl tri¯uoromethyl ketones (1d±g) were synthesized from
the reaction of the respective acetophenone dimethyl acetals
with tri¯uoroacetic anhydride [13,14]. The cyclocondensa-
tion reactions of compounds (1a±g) with thiosemicarbazide
were carried out in a molar ratio of 1:1, using pure methanol
as solvent. The reactions were monitored by TLC and the
most satisfactory reaction time and reaction temperature
were found to be 24 h at 20±258C for 2a±b and 20 h at 40±
458C for 2c±g. It was observed that the compounds (1a) and
(1b) derived from vinyl ethers could be readily converted
into 4,5-dihydro-1H-pirazoles (2a±b) at only ambient
temperature. The same reaction carried out for compounds
(1a±b) at temperature above 358C, led to the polymerization
product. The cyclo-condensation reactions for the propenyl
enol ether and p-substituted acetophenone acetals deriva-
tives (2c±g) with thiosemicarbazide were carried out at
temperature above 408C. This study afforded a methodology
to obtain a series of 3-aryl[alkyl]-5-hydroxy-5-tri¯uoro-
methyl-4,5-dihydro-1H-1-pyrazolethiocarboxyamides
(2a±g) in good to excellent yield (see Table 1). A series
of 3-aryl[alkyl]-5-tri¯uoromethyl-1H-pyrazoles (3a±g) was
obtained by dehydratation and simultaneous removal of the
*Corresponding author. E-mail: heliogb@base.ufsm.br
0022-1139/98/$ ± see front matter # 1998 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 2 4 2 - 5

24
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 92 (1998) 23±26
Scheme 1.
thiocarboxyamide group of compound 2 with sulfuric acid
under re¯ex for 4 h. The crude products were puri®ed by
recrystallization. The crystalline compounds (2a±g) and
(3d±g) are stable in air and may be stored at 20±308C for
months without deterioration. The compounds (3a±c) dar-
kens after 30 days at 0±58C.
All reactions are presented in Scheme 1. The most
satisfactory results of these reactions and the selected
physical data are shown in Tables 1 and 3. Selected
NMR spectral data are presented in Tables 2 and 4.
group with an electron withdrawing effect, hindering
the elimination of water and the subsequent aromatization
of the ®ve-membered ring. The presence of a tri¯uoro-
methyl group on the vinyl ketone (1) and the thiocarbox-
yamide group on the dinucleophile (thiosemicarbazide)
was the determining factor of the regiochemistry of
the reaction. The a-alkyl- and b-alkyl[aryl]-substituent
on the vinyl ketone (1) and the adopted procedures pro-
duced no observable effects on the regiochemistry of the
reaction.
In summary, the use of this methodology developed
in this work allowed the isolation of a new series of 3-
aryl[alkyl]-5-hydroxy-5-tri¯uoromethyl-4,5-dihydro-1H-1-
pyrazolethiocarboxyamides (2) and 3-aryl[alkyl]-5-tri¯uor-
omethyl-1H-pyrazoles (3), which have been prepared in
analytically pure form and in high yield.
3. Conclusion
Our experiments show that the thiocarboxyamide
group on position 1 of the pyrazolines (2) acts as a protective
Table 1
Selected physical data of 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazolethiocarboxyamides (2a±g)
Compound
Yielda
Melting
point (mp)b
(8C)
Molecular formula
and weight
Analysis (%)c calcd/found
(%)
76
C
H
N
2a
2b
2c
2d
2e
2f
139±140
143±144
143±144
158±159
178±179
207±208
235±236
C5H6N3OF3S
213.18
28.17
28.38
31.72
31.85
31.72
31.90
45.67
45.63
47.52
47.65
35.89
35.91
39.50
39.38
2.84
2.82
3.55
3.46
3.55
3.50
3.48
3.47
3.99
3.93
2.46
2.50
2.70
2.88
19.71
19.64
18.49
18.45
18.49
18.17
14.53
14.55
13.85
13.84
11.41
11.40
16.80
16.63
96
74
73
87
87
90
C6H8N3OF3S
227.20
C6H8N3OF3S
227.20
C
11H10N3OF3S
289.28
12H12N3OF3S
303.30
11H9N3OF3SBr
368.17
11H9N4O3F3S
334.27
C
C
2g
C
aYields of isolated compounds.
bThe melting points are uncorrected.
cElemental analysis were performed on a CHN-Elementar Analysensysteme Vario EL.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 92 (1998) 23±26
25
Table 3
Selected physical data of 3-aryl[alkyl]-5-trifluoromethyl-1H-pyrazoles (3a±g)
Compound
Yielda
Melting point (mp)b
Molecular formula
and weight
Analysis (%)c calcd/found
(%)
57
(8C)
C
H
N
3a
3b
3c
3d
3e
3f
44±46
48d
C4H3F3N2
136.08
e
67
72
72
75
75
75
85±87
86±87d
102±104d
C5H5F3N2
150.11
e
e
102±103
122±123
168±169
147±148
154±155
C5H5F3N2
150.11
C
10H7F3N2
212.17
11H9F3N2
226.20
10H6BrF3N2
291.07
10H6F3N3O2
257.17
56.60
56.66
58.40
58.45
41.30
41.00
46.70
46.53
3.30
3.34
4.00
3.92
2.10
2.48
2.40
2.54
13.20
13.11
12.40
12.30
9.60
C
C
9.81
3g
C
16.30
16.15
aYields of isolated compounds.
bThe melting points are uncorrected.
cElemental analysis were performed on a CHN-Elementar Analysensysteme Vario EL.
dData in Ref. [12] led the mp for 3a, 3b and 3c exchanged; they are presented correctly here.
eKnown compounds, see Ref. [12].
Table 2
Selected 1H and 13C NMR spectral dataa of compounds 2a±g
Compound
1H-NMR, ꢀ (ppm), J (Hz)
13C-NMR, ꢀ (ppm), J (Hz)
2a
2b
2c
2d
8.76 (s, 1H, NHa), 8.41 (s, 1H, O±H), 8.24 (s, 1H, NHb), 7.39 (s, 1H, H3), 3.55 (dd, 1H, Jˆ20.0, H4a), 3.34 (dd, 1H, Jˆ20.0, H4b).
177.0 (CˆS), 146.6 (C3), 123.5 (q, Jˆ289.9, CF3), 90.7 (q, Jˆ33.2, C5), 45.7 (C4).
8.58 (s, 1H, NHa), 8.48 (s, 1H, O±H), 8.03 (s, 1H, NHb), 3.51 (d, 1H, Jˆ19.2, H4a), 3.36 (d, 1H, Jˆ19.2, H4b), 2.04 (s, 3H, CH3).
176.0 (CˆS), 156.2 (C3), 123.6 (q, Jˆ289.9, CF3), 91.99 (q, Jˆ32.2, C5), 56.1 (C4), 15.2 (CH3).
8.84 (s, 1H, NHa), 8.78 (s, 1H, O±H), 8.30 (s, 1H, NHb), 7.38 (s, 1H, H3), 3.53 (q, 1H, Jˆ7.4, H4), 1.08 (d, 3H, Jˆ7.4, CH3).
177.1 (CˆS), 151.0 (C3), 123.7 (q, Jˆ290.3, CF3), 90.9 (q, Jˆ32.2, C5), 48.2 (C4), 10.6 (CH3).
8.84 (s, 1H, NHa), 8.50 (s, 2H, NHb e O±H), 7.99 7.87, 7.58 7.40 (m, 5H, aromatic-H), 4.06 (d, 1H, Jˆ20.0, H4a), 3.80 (d, 1H, Jˆ20.0,
H4b).
176.2 (CˆS), 152.6 (C3), 123,5 (q, Jˆ290.3, CF3), 131.2; 129.4; 128.7; 127.3 (aromatic-C), 92.7 (q, Jˆ32.7, C5), 43.9 (C4).
8.82 (s, 1H, NHa), 8.53 (s, 1H, O±H), 8.45 (s, 1H, NHb), 7.83 7.81, 7.31 7.29 (m, 4H, aromatic-H), 4.01 (d, 1H, Jˆ19.0, H4a), 3.75 (d, 1H,
Jˆ19.0, H4b), 2.36 (s, 3H, p-CH3).
2e
2f
176.1 (CˆS), 152.6 (C3), 141.4, 129.3, 127.3, 126.6 (aromatic-C), 123.6 (q, Jˆ289.7, CF3), 92.6 (q, Jˆ33.2, C5), 43.9 (C4), 21.0 (p-CH3).
8.87 (s, 1H, NHa), 8.54 (s, 1H, NHb), 8.49 (s, 1H, O±H), 7.92 7.87, 7.73 7.68 (m, 4H, aromatic-H), 4.07 (d, 1H, Jˆ20.0, H4a), 3.79 (d, 1H,
Jˆ20.0, H4b).
176.3 (CˆS), 151.6 (C3), 131.6, 129.2, 128.6, 124.8 (aromatic-C), 123.4 (q, Jˆ290.3, CF3), 92.9 (q, Jˆ32.2, C5), 43.8 (C4).
8.96 (s, 1H, NHa), 8.66 (s, 1H, NHb), 8.44 (s, 1H, O±H), 8.34 8.30, 8.21 8.17 (m, 4H, aromatic-H), 4.15 (d, 1H, Jˆ19.0, H4a), 3.85 (d, 1H,
Jˆ19.0, H4b).
2g
176.8 (CˆS), 150.6 (C3), 148.5, 135.5, 128.4, 123.7 (aromatic-C), 123.3 (q, Jˆ290.0, CF3), 93.3 (q, Jˆ33.1, C5), 43.8 (C4).
aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13 MHz and 13C at 50.32 MHz) in DMSO-d6/TMS.
4. Experimental
4.1. Preparation of 3-aryl[alkyl]-5-hydroxy-5-
trifluoromethyl-4,5-dihydro-1H-1-
pyrazolethiocarboxyamide (2a±g)
1H- and 13C-NMR spectra, at 200.13 and 50.32 MHz
respectively, were recorded on a Bruker DPX-200 in a 5 mm
probe in DMSO (dimethylsulfoxide)-d6 and TMS was used
as an internal reference. The melting points were taken on
Reichert±Thermovar melting point microscope and are
uncorrected. The elemental analysis were performed on a
CHN-Elementar Analysensysteme Vario EL.
4.1.1. General procedure
To a stirred solution of thiosemicarbazide (10 mmol) in
50 ml of methanol, kept at 20±258C, pure 4-alkoxy-4-aryl-
[alkyl]-1,1,1-tri¯uoro-3-buten-2-one 1a±g (10 mmol) was
added and the mixture was stirred for 24 h at 20±258C for

26
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 92 (1998) 23±26
Table 4
Selected 1H and 13C NMR spectral dataa of compounds 3a±g
Compound
1H-NMR, ꢀ (ppm), J (Hz)
13C-NMR, ꢀ (ppm), J (Hz)
3a
3b
3c
3d
3e
3f
13.57 (s, 1H, NH), 7.86 (d, 1H, Jˆ2.0, H3), 6.60 (d, 1H, Jˆ2.0, H4).
141.3 (q, Jˆ36.7, C5), 130.5 (C3), 122.1 (q, Jˆ267.7, CF3), 103.2 (C4).
13.29 (s, 1H, NH), 6.40 (s, 1H, H4), 2.30 (s, 3H, CH3).
141.2 (q, Jˆ36.2, C5), 140.6 (C3), 122.0 (q, Jˆ267.6, CF3), 102.1 (C4), 10.1 (CH3).
13.29 (s, 1H, NH), 7.73 (s, 1H, H3), 2.12 (s, 3H, CH3).
138.7 (q, Jˆ34.2, C5), 129.8 (C3), 122.5 (q, Jˆ268.7, CF3), 113.5 (C4), 7.62 (CH3).
14.08 (s, 1H, NH), 7.86 7.82, 7.51 7.42 (m, 5H, aromatic-H), 7.19 (s, 1H, H4).
144.2 (C3), 142.2 (q, Jˆ35.2, C5), 121.8 (q, Jˆ268.2, CF3), 129.0, 128.8, 128.3, 125.6 (aromatic-C), 100.9 (C4).
14.01 (s, 1H, NH), 7.75 7.71, 7.32 7.28 (m, 4H, aromatic-H), 7.12 (s, 1H, H4), 2.35 (s, 3H, p-CH3).
144.2 (C3), 141.9 (q, Jˆ38.2, C5), 138.5, 129.6, 125.4 (aromatic-C), 121.8 (q, Jˆ268.2, CF3), 100.5 (C4), 20.7 (p-CH3).
14.17 (s, 1H, NH), 7.84 7.79, 7.73 7.68 (m, 4H, aromatic-H), 7.22 (s, 1H, H4).
142.9 (C3), 142.2 (q, Jˆ37.2, C5), 132.0, 127.4, 127.2, 122.1 (aromatic-C), 121.6 (q, Jˆ268.2, CF3), 101.2 (C4).
14.42 (s, 1H, NH), 8.43 8.30, 8.21 8.09 (m, 4H, aromatic-H), 7.45 (s, 1H, H4).
147.0 (C3), 142.2 (C5), 134.2, 126.4, 124.2 (aromatic-C), 121.4 (q, Jˆ268.3, CF3), 103.0 (C4).
3g
aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13 MHz and 13C at 50.32 MHz) in DMSO-d6/TMS.
2a±b and 20 h at 40±458C for 2c±g. The solvent was
evaporated and hot chloroform was added to the solid
residue. The insoluble thiosemicarbazide was ®ltered off.
The products (2a±g) were crystallized by addition of cyclo-
hexane to the chloroform solution (1:2).
References
[1] D. Lednicer, L.A. Mitscher, Organic Chemistry of Drugs Synthesis,
vol. 1±3, Wiley, New York, 1977.
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4.2.1. General procedure
In a 25 ml ¯ask a mixture of 10 mmol of 3-aryl[alkyl]-5-
hydroxy-5-tri¯uoromethyl-4,5-dihydro-1H-1-pyrazolethio-
carboxyamide (2a±g), and concentrated sulfuric acid
(40 mmol) was stirred at re¯ux for 4 h. The mixture was
poured slowly on 50 ml of ice water and the solution was
extracted with dichloromethane (3Â30 ml). The combined
organic fractions were washed with water, dried with anhy-
drous magnesium sulfate and the solvent removed in a
rotavapor. The solid products 3a±g were recrystallized
hexane or cyclohexane.
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Roberts, Eur. Pat. Appl. EP 295, 117. Chem. Abstr. 112 (1990)
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cyclic Chem. 32 (1995) 735.
[11] N. Zanatta, M.F.M. Cortelini, M.J.S. Carpes, H.G. Bonacorso,
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Acknowledgements
[13] A.F.C. Flores, G.M. Siqueira, R. Freitag, N. Zanatta, M.A.P. Martins,
Quimica Nova 17 (1994) 298.
The authors thank the ®nancial support from the Con-
Â
selho Nacional de Desenvolvimento Cientõ®co e Techno-
logico (CNPq/PADCT III ± Proj. 62.0228/97-0 ± QEQ),
[14] G.M. Siqueira, A.F.C. Flores, G. Clar, N. Zanatta, M.A.P. Martins,
Quimica Nova 17 (1994) 24.
Â
Á
Fundac,aÄo de Amparo a Pesquisa do Estado do Rio Grande
do Sul (FAPERGS). Fellowship from CNPq (A.D.W.) and
FAPERGS (J.A.N.), is also acknowledged.