Synthesis of Some Trifluoromethyl Substituted 1-Methylpyrazoles

Article abstract of DOI:10.1002/jhet.5570400619

The major products from the reaction of β-alkoxyvinyl trifluoromethyl ketones 1a-c with methylhydrazine (2) in absolute ethanol are the 3-(trifluoromethyl)-substituted-1-methylpyrazoles 3a-3c with lesser amounts of the 5-(trifluoromethyl)-substituted prod

Full text of DOI:10.1002/jhet.5570400619

Nov-Dec 2003
1087
Synthesis of Some Trifluoromethyl Substituted 1-Methylpyrazoles
James W. Pavlik [a]*, Theppawut Israsena Na Ayudhya [a]
and Supawan Tantayanon [b]
[a] Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609
[b] Department of Chemistry, Chulalongkorn University, Bangkok, 10330, Thailand
Received July 17, 2003
The major products from the reaction of β-alkoxyvinyl trifluoromethyl ketones 1a-c with methylhydrazine (2) in
absolute ethanol are the 3-(trifluoromethyl)-substituted-1-methylpyrazoles 3a-3c with lesser amounts of the 5-(trifluo-
romethyl)-substituted products 4a-4c and 5a-5c. Carrying out the reaction in non-polar, aprotic solvents can further enhance
the regioselectivity favoring the 3- (trifluoromethyl) -substituted isomers.
J. Heterocyclic Chem., 40, 1087 (2003).
The synthesis of trifluoromethyl substituted 1H-pyra-
romethyl ketones 1a - 1c with methylhydrazine (2) and
have examined the effects of changing the solvent on the
product distributions in these reactions.
zoles has attracted attention because of their potential bio-
logical properties. We have recently reported that reaction
of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1a) with
methylhydrazine (2) in refluxing absolute ethanol leads to
the formation of a mixture of 1-methyl-3-(trifluoro-
methyl)pyrazole (3a) and 4,5-dihydro-1-methyl-5-(trifluo-
romethyl)pyrazol-5-ol (5a) in yields of 52% and 18%
respectively [1]. These two compounds can be readily
Methylhydrazine (2) was allowed to react with
β-alkoxyvinyl trifluoromethyl ketones [2] 1a-c in reflux-
ing absolute ethanol and the crude product mixtures were
subjected to column chromatography on silica gel. Table 1
shows the products formed and their isolated yields and
reveals that in all cases the major products isolated were
the 1-methyl-3-(trifluoromethyl)pyrazoles 3a, 3b, 3c.
Distinction between the regioisomeric 3- and 5-(trifluo-
romethyl)-substituted pyrazoles was unambigouously
separated and 5a undergoes smooth dehydration in CH -
2
Cl /HCl to 1-methyl-5-(trifluoromethyl)pyrazole (4a).
2
These reactions thus allow the convenient synthesis of
pure samples of regioisomers 3a and 4a.
As a result of our interest in the chemistry of trifluo-
romethyl substituted pyrazoles, we have extended these
studies to include the reactions of β-alkoxy vinyl trifluo-
1
13
achieved by the H- and C-NMR data shown in Tables 2
13
and 3. The C-NMR spectra were particularly important
since the pyrazole ring carbons generally appear in the
13
C-NMR spectrum in the order C (furthest upfield) > C
4
5

1088
J. W. Pavlik, T. I. Na Ayudhaya and S. Tantayanon
Vol. 40
Table
4
Table 2
1
Product Distributions in Various SSolvents.
H-NMR Chemical Shifts (δ ppm) of 1-Methylpyrazoles,
Yields (%)
THF
Compound
Ring Position
Reactant Products
EtOH,abs
CH Cl
2
2
3
4
5
N-CH
3
1a +2
3-CF Pyrazole 3a
56
21
9
32
7
66
19
8
60
12
62
0
73
14
7
65
11
68
0
3
3b
4b
3c
4c
-
6.27 (1H)
6.30 (1H)
2.04 (3H)
2.08 (3H)
2.29 (3H)
3.81 (3H)
3.83 (3H)
3.77 (3H)
3.87 (3H)
5-CF Pyrazole 4a
3
2.18 (3H)
-
7.20 (1H)
-
5-CF Pyrazol-5-ol 5a
3
7.10 (1H)
-
1b +2
1c + 2
3-CF Pyrazole 3b
3
5-CF Pyrazole 4b
3
3-CF Pyrazole 3c
40
7
3
5-CF Pyrazole 4c
3
> C (furthest downfield). Accordingly, observation of the
5-CF Pyrazol-5-ol 5c
4
3
3
3
3
long-range carbon-fluorine coupling with the trifluoro-
methyl group was of particular importance in identifying
the regioisomers. Thus, Table 3 shows that in 3b and 3c
These, accordingly, are the 5-trifluoromethyl isomers.
Furthermore, in the case of 3b and 4b, the only signals
observed in the DEPT-90 spectrum were those due to the
C4 carbons confirming that in these compounds the C4
carbon is unsubstituted. In the case of 3c and 4c, however,
the signals due to C5 and C3 respectively were observed in
the DEPT-90 spectrum indicating that these ring positions
were unsubstituted in these isomers.
The structures of 4b and 4c were further confirmed by
showing that these products were chromatographically and
spectroscopically identical to 1,3-dimethyl-5-(trifluo-
romethyl)pyrazole (4b) and 1,4-dimethyl-5-(trifluo-
romethyl) pyrazole (4c) respectively that were regiospecif-
ically synthesized by the procedure shown in Scheme 1
the most downfield signals due to C were observed as
3
quartets indicating that these are both 3-trifluoromethyl
isomers. Conversely, in the case of 4b and 4c, the furthest
downfield signals are all sharp singlets whereas the signals
due to the C carbon at slightly higher field were coupled
5
with the fluorine atoms of the trifluoromethyl group.
Table 3
13
C-NMR Chemical Shifts (δ ppm) of 1-Methylpyrazoles,
Compound
C
C
C
N-CH
39.9
37.5
39.5
37.5
C-CH
11.4
13.5
8.3
CF
3
3
4
5
3
3
3b
4b
3c
4c
141.2,q 104.1 104.5
(J=38Hz)
147.8
121.8,q
(J=268Hz)
120.5,q
(J=268Hz)
122.3,q
(J=269Hz)
120.1,q
(J=269HZ)
107.2 132.7,q
(J=38Hz)
[3]. Although the originally published
procedure [3]
employed a thermal dehydration of the 5-trifluoromethyl-
1-methylpyrazol-5-ols, we observed that treatment of a
dichloromethane solution of 5b or 5c with conc.
hydrochloric acid gives superior results [1].
140.0,q 116.0 131.4
(J=36Hz)
138.3
117.7 127.3,q
(J=38Hz)
7.9

Nov-Dec 2003
Synthesis of Some Trifluoromethyl Substituted 1-Methylpyrazoles.
1089
The crude product from the reaction of methylhydrazine (2)
and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1a) could be sepa-
rated as previously described [1]. Since these techniques invari-
ably resulted in some loss of the volatile 3a, the yields in Table 4
for 3a and 5a were determined by gas-liquid chromatography.
Under these conditions some 5a is dehydrated to 4a, which is not
an observed product by preparative separation techniques [1].
The product distributions resulting from the reactions of
trifluoromethyl ketones 1a-1c with methylhydrazine were
found to be sensitive to the solvent employed. Table 4 thus
shows that the regiochemistry favors formation of the
3-trifluoromethyl substituted pyrazoles 3a, 3b, and 3c as
the solvent is changed from absolute ethanol to tetrahydro-
furan, to dichloromethane. These results suggest that these
reactions involve competition (Scheme 2) between 1,2-
addition, which leads ultimately to the 3-trifluoromethyl
isomers, and 1,4-addition, which places the trifluo-
romethyl group in position 5 of the product. The kineti-
cally controlled 1,2-addition leading to the 3-trifluo-
romethylisomers 3a-c would be expected to be favored in
the less polar, aprotic solvents while the thermodynami-
cally controlled 1,4 addition leading to the 5-trifluo-
romethyl substituted products would be enhanced in the
more polar, protic ethanol solvent.
1,5-Dimethyl-3-(trifluoromethyl)pyrazole (3b) and 1,3-
Dimethyl-5-(trifluoromethyl)pyrazole (4b).
Column Chromatography of the crude product from the reac-
tion of methylhydrazine (2) and 4-methoxy-4-methyl-1,1,1-tri-
fluoro-3-buten-2-one (lb) gave 1,3-dimethyl-5-(trifluo-
romethyl)pyrazole (4b) (first fraction) as an oil: MS: m/z 164
+
(M ); see Tables 2 and 3 for NMR data and 1,5-dimethyl-3-(tri-
fluoromethyl)pyrazole (3b) (second fraction) as an oil: MS: m/z
+
164 (M ); see Tables 2 and 3 for NMR data.
1,4-Dimethyl-3-(trifluoromethylpyrazole (3c), 1,4-Dimethyl-5-
(trifluoromethyl)pyrazole (4c), and 4,5-Dihydro-1,4-dimethyl-5-
(trifluoromethyl)-pyrazol-5-ol (5c).
EXPERMENTAL
Column chromatography of the crude product from the reac-
tion of methylhydrazine (2) and 4-ethoxy-3-methyl-1,1,1-triflu-
oro-3-butene-2-one (1c) gave 1,4-dimethyl-5-(trifluoromethyl)-
1
13
H and C spectra were recorded at 400.1 and 100.6 MHz in
deuteriochloroform on a Bruker FT-NMR system. H and
chemical shifts were measured relative to internal tetramethyl
silane and chloroform respectively. Mass spectra were recorded
with an HP 5970 B mass selective detector interfaced to an HP
588 capillary column gas chromatograph.
+
1
13
pyrazole (4c) (first fraction) as an oil: MS: m/z 164 (M ), see
C
Tables 2 and 3 for NMR data; 1,4-dimethyl-3-(trifluoromethyl)-
+
pyrazole (3c) (second fraction) as an oil: MS: m/z 164 (M ); see
Tables 2 and 3 for NMR data; and 4,5-dihydro-1,4-dimethyl-5-
(trifluoromethyl)pyrazol-5-ol (5c) (third fraction) as a white
1
solid, mp 72-73 °C, lit [3], mp 71-73 °C; H-NMR (deuteriochlo-
General Procedure for the Reaction of Methylhydrazine 2 with
β-Alkoxyvinyl-1,1,1-trifluoro-3-buten-2-ones 1a, 1b, and 1c.
roform): δ 1.17 (d, 3H, J= 7.5 Hz), 2.87 (s, 3H), 3.27 (q, 1H,
13
J=7.5 Hz), 6.5 (S, 1H); C-NMR (deuteriochloroform): δ 9.6,
35.0, 47.6, 98.0 (q, J=29,8 Hz), 124.4(q, J=283 Hz), 145.0.
Methylhydrazine 2 (0.42 g, 9.2 mmol) was added dropwise to a
stirred solution of 1a, 1b, or 1c (6.8 mmol) in the appropriate sol-
vent (Table 4) (4.5 ml) at room temperature. The resulting solu-
tion was stirred and refluxed for 2 hours and then diluted with
dichloromethane (20 ml). The solution was extracted with water
(5 x 5 ml). The combined aqueous phase was saturated with
sodium chloride and extracted with dichloromethane (3x15 ml).
In the reaction when dichloromethane was used as the solvent, no
extraction was needed. The combined organic phase was dried
(sodium sulfate) and concentrated by distillation through a
Vigreux column. The residue was purified by column chromatog-
raphy on silica gel (20 g, 20 cm long x 1.2 cm diameter). The col-
umn was eluted with ethyl acetate (10%)-hexane (90%).
Acknowledgement.
Theppawut Israsena Na Ayudhya acknowledges financial sup-
port from the Development and Promotion of Science and
Technology Talent Project, Bangkok, Thailand.
REFERENCES AND NOTES
[1] J. W. Pavlik, T. Israsena Na Ayudhya and S. Tantayanon,
J. Heterocyclic Chem., 39, 1025 (2002).
[2] A. Colla, M. A. P. Martins, G. Clar, A. Krimmer and
P. Fischer, Synthesis, 483 (1991).
1-Methyl-3-(trifluoromethyl)pyrazole (3a) and 4,5-Dihydro-1-
methyl-5-(trifluoromethyl)-1H-pyrazol-5-ol (5a).
[3] H. G. Bonacorso, A. D. Wastowski, N. Zanatta, and M. A. P.
Martins, Synthetic Communications, 30, 1457 (2000).