Condensation of methylhydrazine with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one. A reinvestigation

Article abstract of DOI:10.1002/jhet.5570390526

In contrast to previous reports, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1) was observed to react with methylhydrazine (2) in refluxing ethanol to yield 1-methyl-3-(trifluoromethyl)pyrazole (6) and 4,5-dihydro-1-methyl-5-(trifluoromethyl)pyrazol-5-ol (4). The later compound undergoes acid catalyzed dehydration to 1-methyl-5-(trifluoromethyl)pyrazole (3).

Full text of DOI:10.1002/jhet.5570390526

Sep-Oct 2002
Condensation of Methylhydrazine with 4-Ethoxy-
1,1,1-Trifluoro-3-buten-2-one. A Reinvestigation
1025
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 March 20, 2002
In contrast to previous reports, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1) was observed to react with
methylhydrazine (2) in refluxing ethanol to yield 1-methyl-3-(trifluoromethyl)pyrazole (6) and 4,5-dihydro-
1-methyl-5-(trifluoromethyl)pyrazol-5-ol (4). The later compound undergoes acid catalyzed dehydration to
1-methyl-5-(trifluoromethyl)pyrazole (3).
J. Heterocyclic Chem., 39, 1025 (2002).
Braibante, Martins, and colleagues have reported that
carbons, respectively. In addition, the spectrum also
reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1) with
methylhydrazine (2) in refluxing ethanol leads to the
formation of 1-methyl-5-(trifluoromethyl)pyrazole (3) in
78% yield [1]. This reaction presumably occurs, as shown
in Scheme 1, via the intermediacy of 4,5-dihydro-1-
methyl-5-(trifluoromethyl)pyrazole-5-ol (4). Although 4
was reportedly not an isolable product in this reaction,
shows signals at δ 104.9, 131.8, and 142.7 for the three
carbons of the pyrazole ring. Based on the C-NMR
13
spectra of other 1-methylpyrazoles these signals can be
assigned to the carbons at ring positions 4, 5, and 3
respectively since the C-4 carbon of the pyrazole ring
absorbs furthest upfield whereas the C-3 carbon is
generally observed furthest downfield. Interestingly, it
Bonacorso, Martins, and colleagues subsequently reported
(Scheme 2) that 4 could be formed in 86% yield by treating
the analogous 1-pyrazolethiocaboxamide (5) with methyl-
hydrazine (2) in THF at 25 C [2]. Formed in this way, 4
was reported to undergo dehydration when heated to
100-130 C to provide 3 in unspecified yield.
We wish to report that in our laboratory reaction of 1 [3]
and 2 in refluxing absolute ethanol led to different results.
After refluxing a solution of 1 and 2 in absolute ethanol [4]
as previously described [1], tlc examination revealed the
formation of two products which could be separated by
column chromatography on silica gel, or more readily, by
using their greatly different volatilities.
is the signal for the C-3 carbon at δ 142.7 that appeared
as a quartet (J = 38 Hz) due to long-range coupling with
the fluorine nuclei of the trifluoromethyl group whereas
the signal due to the C-5 carbon at δ 131.8 appeared as a
sharp singlet. This shows that the trifluoromethyl
substituent is at ring position 3 and identifies this
product as 1-methyl-3-(trifluoromethyl)pyrazole (6).
Indeed, Bonacorso and colleagues reported that the
compound they isolated from the dehydration of
4,5-dihydro-1-methyl-5-(trifluoromethyl)pyrazol-5-ol
The more volatile component of this mixture was
obtained as an oil. Gas liquid partition chromatography
(Glpc) of this oil showed a single volatile component.
The mass spectrum of this compound exhibited a mole-
cular ion at m/z 150 as expected for a trifluoromethyl
1
substituted 1-methylpyrazole. The H-NMR spectrum
13
of the oil exhibited a 3H singlet at δ 3.86, a 1H doublet
(J = 2.0 Hz) at δ 6.58, and a 1H broad singlet at δ 7.40
also consistent with a mono-substitued-1-methylpyra-
(4) exhibited signals in the C-NMR spectrum at δ
107.5 (C-4), 131.9 (C-5), and 138.1 (C-3) [2]. In this
case, it was the signal at δ 131.9 for C-5 which
exhibited the long-range coupling (J = 39 Hz). This
confirms that these workers isolated 1-methyl-5-
(trifluoromethyl)pyrazole (3) from the dehydration of 4.
13
zole [6]. The C-NMR spectrum of this compound
exhibited a singlet at δ 39.6 and a quartet (J = 266.6 Hz)
at δ 121.7 due to the N-methyl and trifluoromethyl

1026
J. W. Pavlik, T. I. Na Ayudhya and S. Tantayanon
Vol. 39
The less volatile component of the mixture was obtained
1H doublet (J = 1.2 Hz) at δ 6.52 and a broad 1H singlet at
δ 7.39, almost indistinguishable from the H-NMR
1
as a white crystalline compound, which melted at 69-70 C.
Glpc-mass spectroscopic analysis with an oven
temperature of 70 C showed a single volatile compound
with a retention time of 14 minutes. The mass spectrum
exhibited a molecular ion at m/z 168, consistent with a
hydrated product, and a base peak at m/z 150, which
indicates that the major fragmentation pathway involves
dehydration. Interestingly, when the analysis was carried
out at an oven temperature of 100 C, Glpc showed that the
compound with a retention time of 14 minutes was
replaced by a single peak with a retention time of 7 min-
utes. The mass spectrum of this compound exhibited a
molecular ion at m/z 150 with no sign of the signal at m/z
168. This indicates that at the higher oven temperature
dehydration occurs in the column and that the hydrated
compound never reaches the detector.
spectrum of 1-methyl-3-(trifluoromethyl)pyrazole (6). The
13
C-NMR spectrum, however, clearly shows that this
compound is 1-methyl-5-(trifluoromethyl)pyrazole (3).
Thus, in addition to singlets at δ 38.8 (N-methyl) and δ
107.9 (C-4 ring carbon) and a quartet (J = 268.3 Hz) at δ
13
120.6 (trifluoromethyl carbon), the C spectrum also
showed that the most downfield carbon due to the C-3 ring
carbon appeared as a sharp singlet at δ 138.5 while the
signal due to the C-5 ring carbon appeared upfield at δ
132.2 as a quartet (J = 39.2 Hz). This confirms that in this
product the trifluoromethyl substituent is bonded to the
C-5 ring carbon.
These results indicate that reaction of vinyl ketone 1
with methylhydrazine (2) involves a competition of
Michael attack by both the primary and secondary nitrogen
atoms of 2 and subsequent cyclization, as shown in
Scheme 3, to 4,5-dihydro-1-methyl-5-(trifluoromethyl)-
pyrazol-5-ol (4) and 4,5-dihydro-1-methyl-3-(trifluoro-
methyl)pyrazol-5-ol (7). Dehydration of either 4 or 7
would be accompanied by development of a positive
charge at C-5 of the dihydropyrazole ring. In both 4 and 7
this positive charge would be stabilized by resonance
interaction with the adjacent non-bonded electrons on
nitrogen. In the case of 4, however, the charge would be
significantly destabilized by the trifluoromethyl group at
C-5. This destabilization would increase the energy barrier
to dehydration. As a result, 4 is sufficiently stable to allow
its isolation. In contrast, the trifluoromethyl group at
position 3 is expected to have little effect on the
developing positive charge at C-5 in 7, which therefore is
not isolated but undergoes spontaneous dehydration to
pyrazole 6.
This data indicates that this product is 4,5-dihydro-1-
methyl-5-(trifluoromethyl)pyrazol-5-ol (4) [2]. The NMR
spectra are consistent with this assignment. Thus, as
1
demanded by the structure, the H-NMR spectrum
exhibited a 3H singlet at δ 2.95 for the protons of the
N-methyl group, a pair of 1H doublets (J = 18.7 Hz) at δ
2.89 and 3.20 for the two non-equivalent protons at C-4,
and a 1H singlet at δ 6.67 due to the imine proton at C-3.
13
The C-NMR spectrum was also consistent with the
assigned structure and showed singlets at δ 34.5 due to the
N-methyl carbon, at δ 45.0 due to the C-4 ring carbon, and
at δ 139.1 due to the C-3 imine carbon. As expected by
these assignments only the signal at 45.0 was negative in
the DEPT-135 spectrum confirming that this signal is due
to a methylene carbon. In addition to these singlets, the
13
C-NMR spectrum also exhibited one quartet (J =
282.7 Hz) at δ 124.0 and a second quartet (J = 31.4 Hz) at
δ 92.0 due to the trifluoromethyl and C-5 ring carbons
respectively.
The ratio of the yields of 6:4 was observed to vary over
the range from 2.9:1 to 2.1:1. The factors controlling the
regioselectivity of this and the reactions of methyl-
hydrazine (2) with other related trifluoro-substituted vinyl
ketones is currently under investigation and will be
reported at a later time.
4,5-Dihydro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-
5-ol (4) was found to undergo smooth dehydration upon
treatment with methylene chloride – conc. hydrochloric
1
acid at room temperature [7]. The H-NMR spectrum of
the resulting oil [8] exhibited a 3H singlet at δ 3.91 and a

Sep-Oct 2002
Condensation of Methylhydrazine with 4-Ethoxy-1,1,1-Trifluoro
1027
EXPERIMENTAL
H and C spectra were recorded at 400.1 and 100.6 MHz in
room temperature. After stirring for 30 minutes saturated
aqueous sodium bicarbonate (25 ml) was added. The organic
layer was separated, dried (sodium sulfate) and concentrated by
distillation. The residue (823 mg) was connected to a vacuum
line and pumped down to 0.1-1.0 Torr. The effluent from the flask
containing the residue was passed through a glass trap submerged
in a dry ice-acetone bath. After 30 minutes the trap contained
1-methyl-5-(trifluoromethyl)pyrazol (3) as an oil (732 mg,
1
13
1
13
deuteriochloroform on a Bruker FT-NMR system. H and
C
chemical shifts were measured relative to internal tetramethyl-
silane and chloroform, respectively. Mass spectra were recorded
with an HP 5970B mass selective detector interfaced to an HP
588 capillary gas chromatograph.
1
4.9 mmol, 80%): H-NMR (deuteriochloroform): δ 3.91 (s, 3H),
1-Methyl-3-(trifluoromethyl)pyrazole (6) and 4,5-Dihydro-1-
methyl-5-(trifluoromethyl)-1H-pyrazol-5-ol (4).
13
6.52 (d, 1H, J = 1.2 Hz), 7.39 (br. s, 1H); C-NMR (deuterio-
chloroform): δ 38.8, 107.9, 120.6 (q, J = 268 Hz), 132.2 (q, J = 39
Hz), 138.5.
Methylhydrazine (2) (1.5 g, 33.0 mmol) was added dropwise to a
stirred solution of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1)
(4.12 g, 24.5 mmol) in absolute ethanol (16 ml) at room temperature.
The resulting solution was stirred and refluxed for 2 hours and then
diluted with dichloromethane (20 ml). The solution was extracted
with water (5x5 ml). The aqueous phase was saturated with sodium
chloride and extracted with dichloromethane (3x15 ml). The
combined organic phase was dried (sodium sulfate) and concen-
trated by distillation through a vigreux column. The residue (3.2 g)
was connected to a vacuum line and pumped down to 0.1-1.0 Torr
[9]. The effluent from the flask containing the residue was passed
through a glass trap submerged in a dry ice-acetone bath. After
3 hours the trap contained 1-methyl-3-(trifluoromethyl)pyrazole (6)
Acknowledgement.
Theppawut Israsena Na Ayudhya acknowledges financial
support from The Development and Promotion of Science and
Technology Talent Project, Bangkok, Thailand.
REFERENCES AND NOTES
[1] M. E. F. Braibante, G. Clar, and M. A. P. Martins,
J. Heterocyclic Chem., 30, 1159 (1993).
[2] H. G. Bonacorso, A. D. Wastowski, N. Zanatta, and
M. A. P. Martins, Synth. Commun., 30, 1457 (2000).
[3] A. Colla, M. A. P. Martins, G. Clar, S. Krimner, and P. Fischer,
Synthesis, 483 (1991).
[4] Commercially available absolute ethanol was further
purified by refluxing over magnesium ethoxide followed by fractional
distillation [5].
[5] A. Lund and J. Bejerrum, Ber., 64B, 210 (1931).
[6] Y. Kamitori, M. Hojo, R. Masuda, M. Fujishiro, and M. Wada,
Heterocycles, 38, 21 (1994), See reference 3.
1
as an oil (1.9 g, 12.7 mmol, 52%); H-NMR (deuteriochloroform): δ
13
3.86 (s, 3H), 6.58(d, 1H, J = 2.0 Hz), 7.32 (br. s, 1H), lit [4]; C-
NMR (deuteriochloroform): δ 39.8, 104.9, 121.7 (q, J = 267 Hz),
+
131.8, 142.7 (q, J = 37.9 Hz); ms: m/z 150 (M ). The non-volatile
residue (1.07 g) was crystallized from dichloromethane to give 4,5-
dihydro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-ol (4) as white
crystals (739 mg, 4.4 mmol, 18%) mp 69-70 C, lit [2], mp 75-76 C;
1
H-NMR (deuteriochloroform): δ 2.95 (s, 3H), 2.89 (d, 1H, J = 18.8
[7] J. W. Lyga and R. M. Patera, J. Heterocyclic Chem., 27, 919
(1990).
[8] This compound was inexplicably reported in reference 1 to
have a melting range of 68-70 C.
13
Hz), 3.20 (d, 1H, J = 18.8 Hz), 6.67 (s, 1H); C-NMR (deuterio-
chloroform): δ 34.5, 45.0, 92.0 (q, J = 31.4 Hz), 124.0 (q, J = 283
+
+
Hz), 139.1; ms (70 C): m/z 168 (M ); ms (100 C): m/z 150 (M ).
[9] 1-Methyl-3-(trifluoromethyl)pyrazole (6) and 4,5-dihydro-1-
methyl-5-(trifluoromethyl)pyrazol-5-ol (4) could also be separated by
column chromatography on silica gel. Elution with ethyl acetate (10%)-
hexane (90%) gave 6 (first fraction) and 4 (second fraction) in yields of
6% and 23% respectively.
1-Methyl-5-(trifluoromethyl)pyrazole (3).
Concentrated hydrochloric acid (6 drops) was added to a
stirred solution of 4,5-dihydro-1-methyl-5-(trifluoromethyl)-1H-
pyrazol-5-ol (4) (1.03 g, 6.1 mmol) in dichloromethane (30 ml) at