Fluorine-sacrificial cyclizations as an access to 5-fluoropyrazoles

Article abstract of DOI:10.1002/(SICI)1099-0690(200003)2000:5<823::AID-EJOC823>3.0.CO;2-M

Methyl 3-methoxy-2-trifluoromethylacrylate 1, readily prepared by Wittig reaction from methyl 3,3,3-trifluoropyruvate, has been treated with a number of aryl- (or hetaryl-) hydrazines. Under mild base-catalysis, the resulting 3-hydrazinoacrylates 6 underg

Full text of DOI:10.1002/(SICI)1099-0690(200003)2000:5<823::AID-EJOC823>3.0.CO;2-M

FULL PAPER
Fluorine-Sacrificial Cyclizations as an Access to 5-Fluoropyrazoles
[a]
[a]
¨
Jean-Noel Volle and Manfred Schlosser*
Keywords: Fluorine-containing heterocycles / Methyl trifluoropyruvate / Fluoride elimination / Cyclization reactions /
Hydrazone / Hydrazine tautomerism
Methyl 3-methoxy-2-trifluoromethylacrylate 1, readily pre-
pared by Wittig reaction from methyl 3,3,3-trifluoropyruvate,
methyl 1-(het)aryl-5-fluoropyrazole-4-carboxylates 7. 5-Ami-
nopyrazoles 8 have been obtained by direct reaction of the
has been treated with a number of aryl- (or hetaryl-) hydra- ester 7a with a lithium amide, whereas 5-fluoro-1-phenylpyr-
zines. Under mild base-catalysis, the resulting 3-hydrazi-
noacrylates 6 undergo consecutive hydrogen fluoride elim-
ination and intramolecular nucleophilic addition to afford
azole-4-carboxamides 10 have been formed by condensation
of the 5-fluoro-1-phenylpyrazole-4-carboxylic acid 9 with
amines.
Introduction
Previously, this laboratory has devoted considerable ef-
fort towards the preparation of ’’fluoroisoprene’’ (2-fluoro-
3-methyl-1,3-butadiene)[1–3] and its homologues,[2–5] includ-
ing congeners bearing electron-withdrawing[2,6] and elec-
tron-donating[6–9] heterofunctional groups, as well as 2-
fluoro-2-alkenals[10] and the corresponding N-tert-butyl
imines[11] and N,N-dimethylhydrazones.[12] These fluorinated
building blocks have been employed as versatile modules in
chain-lengthening (‘‘fluoroisoprenylation’’)[11] or Diels–
Alder cycloaddition[2,4,7,8,12] reactions. More recently, the
acyl chloride and the methyl ester of 2-fluoro-3-methoxy-
acrylic acid have been used as electrophilic components in
Knorr–Effenberger type and other cyclization reactions, al-
lowing access to a host of fluorine-bearing pyrazolones,
uracils, 2-quinolones, 2-chromenones (2H-1-benzopyran-2-
Upon gentle warming, ester 1 underwent a condensation
reaction with aniline to afford (E)-methyl 3-anilino-2-tri-
fluoromethyl-2-propenoate (2a; 92%). Heating this interme-
diate to 100 °C in the presence of polyphosphoric acid gave
4-quinolone as the sole identifiable product (3a; 24%). Ap-
parently, repeated 1,4-dehydrofluorination followed by ad-
dition of water led to a transformation of the trifluorome-
thyl substituent into a carboxy function and then the latter
was lost in a typical β-oxo-assisted decarboxylation process.
With N-methylaniline, the reaction sequence took a slightly
different course. (N-Methylanilido)acrylate (2b; 52%), de-
rived from this amine as a 1:4 (Z/E) mixture, was converted
into methyl 1-methyl-4-quinolone-3-carboxylate (3b; 44%)
as the major cyclization product. Lastly, methyl 3-(2-amino-
phenyl)amino-2-trifluoromethyl-2-propenoate (4; 89%) and
ones),
1-thio-2-chromenones,
and
benzothiazepin-
ones.[9,13,14]
We decided to prepare methyl 3-methoxy-2-trifluorome-
thyl-2-propenoate (1) in order to extend the latter studies
towards the assembly of trifluoromethyl-substituted hetero-
cycles. We had hitherto gained access to this class of com-
pounds through the use of two other building blocks,
namely
3-trifluoromethyl-1-trimethylsilyloxy-1,3-butadi-
ene[15] and 4-tert-butylamino-1,1,1-trifluoro-3-buten-2-
one,[16,17] a synthetic equivalent of 4,4,4-trifluoro-3-oxobut-
anal.
The required key intermediate 1 was readily obtained by
a Wittig reaction between methyl 3,3,3-trifluoropyruvate
(methyl 3,3,3-trifluoro-2-oxopropanoate)[18,19] and (triphen-
ylphosphonio)methoxymethanide.[20,21] The product was
isolated as a 2:3 (Z/E) mixture and was used as such in all
subsequent reactions.
methyl
1H-4-isopropyloxy-1,5-benzodiazepine-3-carb-
oxylate (5b; 7%) were obtained when 1,2-phenylenediamine
was employed as the starting material.
Fluoride elimination/nucleophile addition sequences are
responsible for the lability of 2- and 4-(trifluoromethyl)-
phenol under basic conditions.[22,23] Similar transforma-
tions of trifluoromethyl groups by two-step nucleophilic
substitutions have been reported for 4-(trifluoromethyl)ani-
[a]
´
Section de Chimie (BCh), Universite,
CH-1015 Lausanne, Switzerland
Fax: (internat.) ϩ 41-21/692 39 65
Eur. J. Org. Chem. 2000, 823Ϫ828
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0305Ϫ0823 $ 17.50ϩ.50/0
823

J.-N. Volle, M. Schlosser
FULL PAPER
cess to 5-fluoropyrazole derivatives. When the ester 1 was
heated in the presence of an aryl- (or hetaryl)- hydrazine,
smooth replacement of the methoxy group occurred. The
methyl 3-(het)arylhydrazino-2-(trifluoromethyl)acrylates 6
thus formed were found to exist in equilibrium with the
tautomeric species 6’. Fluorine-sacrificial cyclization oc-
curred under weakly basic conditions, a first elimination of
hydrogen fluoride initiating intramolecular addition of the
terminal nitrogen atom to the halogen-bearing carbon, and
a second one, as the last stage of the ring-closure process,
affording
methyl
1-(het)aryl-5-fluoropyrazole-4-carb-
oxylates 7 as the final products.
line,[24,25] 4-(nonofluorobutyl)aniline,[26] 2- and 3-(trifluoro-
methyl)indole,[27,28] and 5-amino-2-chloro-4-(trifluorome-
thyl)thiazole.[29] The irreversible inhibition of decarb-
oxylases, transaminases, and racemases by a variety of β-
fluoroamines also involves the elimination of hydrogen flu-
oride and subsequent binding to the enzyme through a cys-
teine residue.[30] 1-(2-Hydroxyphenyl)-2,3,3,3-tetrafluoro-
propanone[31,32] and N-(2-hydroxyphenyl)-2,2,2-trifluoro-1-
(trifluoromethyl)ethylamine[33] undergo base-promoted de-
hydrofluorination followed by intramolecular nucleophilic
attack of the phenolate oxygen to afford a 2-substituted
3-fluoro-4H-1-benzopyran-4-one (a chromenone) and 2-
fluoro-3-trifluoromethyl-1,4-benzoxazine, respectively. N-
Alkylidene-2-(trifluoromethyl)anilines react with nucleo-
philes such as butyllithium, lithium diisopropylamide, or
potassium tert-butoxide to afford quinolines bearing the nu-
cleophile moiety at the 4-position.[34–37] 4-Fluoroquinolines
can be prepared by trapping of (6-difluoromethylene-2,4-
cyclohexadienylidene)amine, generated from 2-(trifluoro-
methyl)aniline, with nucleophiles such as acetylides, enol-
ates, or eneimides (α-deprotonated aliphatic nitriles).[26,38]
Other methods involving dehydrofluorination and cycliza-
tion through intramolecular nucleophilic addition lead to
1,2-dihydro-3-trifluoromethyl-4-pyridazinones,[39] to 2-
fluoroindoles, -benzofurans, and -benzothiophenes,[40] and
to 3-trifluoromethyl- (or 3-perfluoroalkyl-), 4-fluoro-, or
When solutions of ester 7a and lithium anilide or lithium
both 3-trifluoromethyl- and 4-fluoro-substituted pyra- p-anisidide in tetrahydrofuran were mixed, the methyl 5-
zoles.[41–43]
amino-1-phenylpyrazole-4-carboxylates 8a (84%) and 8b
It became apparent that methyl 3-methoxy-2-(trifluoro- (74%) were rapidly formed in a nucleophilic 1,4-addition/
methyl)acrylate (1) described above offers a convenient ac- fluoride elimination sequence. Alternatively, ester 7a could
824
Eur. J. Org. Chem. 2000, 823Ϫ828

Fluorine-Sacrificial Cyclizations as an Access to 5-Fluoropyrazoles
FULL PAPER
Methyl 3-Methylanilino-2-trifluoromethyl-2-propenoate (2b): The
above procedure was repeated by using N-methylaniline (3.3 mL,
3.2 g, 30 mmol) instead of aniline and heating at 100 °C was pro-
longed to 5 h. The corresponding substitution product, isolated by
column chromatography, was found to exist as a 1:4 (Z/E) mixture;
be saponified to give the carboxylic acid 9, and the latter
could then be converted into the carboxamides 10 by con-
densation with various aromatic amines in the presence of
(1-benzotriazolyloxy)tripyrrolidinophosphonium
hexa-
fluorophosphate (BTP-HFP).[44]
1
b.p. 98–99 °C/0.8 Torr; 4.0 g (52%). – H NMR of Z-2b: δ ϭ 7.97
The new access to 5-fluoropyrazoles 7 reported herein
has its limitations. We were unable to isolate any heterocyc-
lic compounds following attempted reactions between ac-
rylate 1 and alkylhydrazines. We are currently focussing on
(q, J ϭ 1.5 Hz, 1 H), 7.4 (m, 5 H), 3.76 (s, 3 H), 3.46 (q, J ϭ
1
3.0 Hz, 3 H). – H NMR of E-2: δ ϭ 7.3 (m, 6 H), 3.69 (s, 3 H),
3.38 (s, 3 H). – 19F NMR of Z-2b: δ ϭ –51.3 (s). – 19F NMR of
E-2b: δ ϭ –59.0 (s). – C12H12F3NO2 (259.23): calcd. C 55.60, H
acylhydrazines and hydroxylamines as potential cyclization 4.66; found C 55.61, H 4.75.
components.
Methyl 3-(2-Aminoanilino)-2-trifluoromethyl-2-propenoate (4): A
similar reaction as above was performed with 1,2-phenylenedi-
amine (3.2 g, 30 mmol), but this substrate was dissolved together
with the acrylate 1 in methanol (100 mL) and the resulting solution
was heated under reflux for 2 h. After evaporation of the solvent,
the crude product was purified by chromatography on silica, again
by using a 1:20 (v/v) mixture of ethyl acetate and hexanes as eluent;
m.p. 113–115 °C (from hexanes); 6.9 g (89%). – 1H NMR: δ ϭ
10.24 (br. d, J ϭ 13.0 Hz, 1 H), 7.73 (dd, J ϭ 13.0, 1.0 Hz, 1 H),
7.0 (m, 2 H), 6.85 (td, J ϭ 7.5, 1.0 Hz, 1 H), 6.81 (dd, J ϭ 8.0,
1.0 Hz, 1 H), 3.84 (s, 3 H), 3.63 (br. s, 2 H). – 19F NMR: δ ϭ –
60.2 (d, J ϭ 1.0 Hz). – MS (CI): m/z (%) ϭ 278 (12) [Mϩ ϩ NH4],
261 (100) [Mϩ ϩ 1], 260 (22) [Mϩ], 241 (35), 119 (49). –
C11H11F3N2O2 (260.21): calcd. C 50.77, H 4.26; found C 50.98,
H 3.89.
Experimental Section
General Remarks: For standard operations and abbreviations, refer
to recent publications from this laboratory.[45,46] 1H- and 19F NMR
spectra were recorded in deuteriochloroform solution at 400 and
376 MHz, respectively. Mass spectra were obtained after chemical
ionization (CI) and only 35Cl isotopomers are listed in the case of
chlorinated compounds.
Preparation of the Key Starting Material: Methyl 3-Methoxy-2-tri-
fluoromethyl-2-propenoate (1): (Methoxymethyl)triphenylphos-
phonium bromide (58 g, 0.15 mol) was added to a solution of tert-
butyllithium (0.15 mol) in a 2:1 mixture (250 mL) of tetrahydrofu-
ran and pentane cooled to –75 °C. After stirring vigorously for
15 min at –25 °C, the mixture was cooled to –75 °C once more,
whereupon methyl trifluoropyruvate[18,19] (23 g, 0.15 mol) was ad-
ded. The reaction mixture was allowed to warm to 25 °C and then
poured into cold (–25 °C) pentane (250 mL). After the addition of
diatomaceous earth (kieselguhr), the solid material was removed by
suction filtration and the filtrate was concentrated. On distillation
under reduced pressure, a colorless liquid was collected; 14.1 g
(51%); b.p. 79–81 °C/5 Torr. – C6H7F3O3 (184.11): calcd. C 39.14,
H 3.83; found C 39.31, H 3.93.
4H-4-Quinolinone (3a): The 3-aminoacrylate 2a (2.5 g, 10 mmol)
was added to polyphosphoric acid (15 mL) and the mixture was
heated at 100 °C for 1 h. Neutralization, extraction, and sub-
sequent chromatography (see above) afforded 4-quinolinone (4-hy-
droxyquinoline) as a white solid; m.p. and mixed m.p. 194–197 °C
(ref.[47] 196–197 °C); 0.35 g (24%; 22% based on 1).
Methyl 1,4-Dihydro-1-methyl-4-oxoquinoline-3-carboxylate (3b):
Analogous treatment of aminoacrylate 2b (10 mmol) afforded the
ester 3b; m.p. 189–191 °C (after sublimation; ref.[48] 185–186 °C);
1
0.50 g (44%; 23% based on 1). – H NMR: δ ϭ 8.51 (dd, J ϭ 8.0,
1.5 Hz, 1 H), 8.46 (s, 1 H), 7.70 (ddd, J ϭ 8.0, 7.0, 1.5 Hz, 1 H),
7.4 (m, 2 H), 3.92 (s, 3 H), 3.88 (s, 3 H). – MS (CI): m/z (%) ϭ 218
(100) [Mϩ ϩ 1], 217 (18) [Mϩ], 186 (35), 159 (55).
On the basis of gas chromatographic (30 m, DB-1701, 100 °C; 30
m, DB-FFAP, 100 °C) and NMR analyses, the product was found
Methyl 4-Isopropyloxy-1H-1,5-benzodiazepine-3-carboxylate (5b):
The aminoacrylate 4 (10 mmol) was added to a suspension of po-
tassium carbonate (2.8 g, 20 mmol) in propan-2-ol (100 mL). The
mixture was heated under reflux for 45 min, the solvent was then
evaporated, and the product was isolated by chromatography; m.p.
1
to consist of the (Z) and (E) isomers in a 2:3 ratio. – H NMR of
1
Z-1: δ ϭ 7.24 (q, J ϭ 1.5, 1 H), 4.02 (s, 3 H), 3.80 (s, 3 H). – H
NMR of E-1: δ ϭ 7.62 (s, 1 H), 4.01 (s, 3 H), 3.78 (s, 3 H). – 19F
NMR of Z-1: δ ϭ –61.8 (d, J ϭ 1.5 Hz). – 19F NMR of E-1: δ ϭ
–58.8 (s). – MS (CI, GC-coupled) of Z-1: m/z (%) ϭ 202 (46) [Mϩ
ϩ NH4], 185 (83) [Mϩ ϩ 1], 184 (16) [Mϩ], 153 (100). – MS (CI,
GC-coupled) of E-1: m/z (%) ϭ 202 (63) [Mϩ ϩ NH4], 185 (35)
[Mϩ ϩ 1], 184 (20) [Mϩ], 153 (100).
1
170–171 °C (after sublimation); 0.18 g (7%; 6% based on 1). – H
NMR: δ ϭ 7.47 (d, J ϭ 8.0 Hz, 1 H), 7.0 (m, 1 H), 6.88 (dd, J ϭ
8.0, 1.5 Hz, 1 H), 6.82 (td, J ϭ 8.0, 1.5 Hz, 1 H), 6.36 (dd, J ϭ 8.0,
1.5 Hz, 1 H), 5.38 (br. d, J ϭ 8.0 Hz, 1 H), 5.24 (sept, J ϭ 6.3 Hz,
1 H), 3.69 (s, 3 H), 1.31 (d, J ϭ 6.3 Hz, 6 H). – MS (CI): m/z (%) ϭ
261 (79) [Mϩ ϩ 1], 260 (47) [Mϩ], 219 (50), 186 (49), 119 (100). –
C14H16N2O3 (260.29): calcd. C 64.60, H 6.20; found C 65.19, H
5.66.
3-Amino-2-(trifluoromethyl)acrylates and Cyclization Products De-
rived Therefrom: Methyl 3-Anilino-2-trifluoromethyl-2-propenoate
(2a): A mixture of methyl 3-methoxy-2-trifluoromethyl-2-propeno-
ate 1 (5.5 g, 30 mmol) and aniline (2.7 mL, 2.8 g, 30 mmol) was
heated at 100 °C for 1 h. The product was then absorbed on silica
and eluted with a 1:20 mixture (v/v) of ethyl acetate and hexanes.
Upon recrystallization of the white solid from hexanes, colorless
needles were obtained; m.p. 68–70 °C; 6.8 g (92%). – 1H NMR:
δ ϭ 10.47 (br. d, J ϭ 13.3 Hz, 1 H), 7.85 (d, J ϭ 13.3 Hz, 1 H),
3-N’-(Het)Arylhydrazino-2-(trifluoromethyl)acrylates and Cycliza-
tion Products Derived Therefrom: Methyl 3-N’-Phenylhydrazino-2-
trifluoromethyl-2-propenoate (6a): A mixture of the acrylate 1
(7.4 g, 40 mmol) and phenylhydrazine (3.9 mL, 4.3 g, 40 mmol) was
heated under reflux for 2 h. A 2:1 mixture of the 3-hydrazinoacryl-
ate 6a and the 3-hydrazonopropionate 6a’ was obtained; 8.6 g
1
7.36 (t, J ϭ 7.9 Hz, 2 H), 7.14 (t, J ϭ 7.9 Hz, 1 H), 7.06 (d, J ϭ (83%) after purification by chromatography on silica. – H NMR:
7.9 Hz, 2 H), 3.84 (s, 3 H). – 19F NMR: δ ϭ –60.0 (s). – MS (CI):
δ ϭ 9.45 (br. d, J ϭ 10.9 Hz, 0.7 H), 7.79 (s, 0.3 H), 7.54 (d, J ϭ
m/z (%) ϭ 263 (33) [Mϩ ϩ NH4], 246 (100) [Mϩ ϩ 1], 245 (20) 10.9 Hz, 0.7 H), 7.26 (t, J ϭ 7.9 Hz, 2 H), 7.0 (m, 1.6 H), 6.89 (t,
[Mϩ], 226 (90). – C11H10F3NO2 (245.20): calcd. C 53.88, H 4.11;
found C 53.73, H 4.15.
J ϭ 7.4 Hz, 0.3 H), 6.78 (d, J ϭ 7.9 Hz, 1.4 H), 6.09 (br. s, 0.7 H),
4.13 (qd, J ϭ 8.5, 1.0 Hz, 0.3 H), 3.80 (s, 0.9 H), 3.78 (s, 2.1 H).
Eur. J. Org. Chem. 2000, 823Ϫ828
825

J.-N. Volle, M. Schlosser
FULL PAPER
When the tautomeric mixture was triturated with pentanes, the
pure hydrazino derivative 6a crystallized; 39%; m.p. 97–99 °C (after
sublimation). – 19F NMR: δ ϭ –60.3 (s). – MS (CI): m/z (%) ϭ
silica by using a 1:9 (v/v) mixture of ethyl acetate and hexanes as
eluent; 3.5 g (79%). An additional sublimation was required to ob-
tain the product in a colorless state; m.p. 82–83 °C. – 1H NMR:
278 (22) [Mϩ ϩ NH4], 261 (94) [Mϩ ϩ 1], 260 (10) [Mϩ], 241 (23), δ ϭ 7.96 (d, J ϭ 2.5 Hz, 1 H), 7.64 (dd, J ϭ 7.9, 1.3 Hz, 2 H), 7.51
94 (100). – C11H11F3N2O2 (260.21): calcd. C 50.77, H 4.26; found
C 50.91, H 4.20.
(t, J ϭ 7.9 Hz, 2 H), 7.41 (t, J ϭ 7.9 Hz, 1 H), 3.88 (s, 3 H). – 19F
NMR: δ ϭ –123.3 (m). – MS (CI): m/z (%) ϭ 238 (5) [Mϩ
ϩ
NH4], 221 (100) [Mϩ ϩ 1], 220 (37) [Mϩ], 189 (26). – C11H9FN2O2
Methyl
3-N’-(2-Fluorophenyl)hydrazino-2-trifluoromethyl-2-pro-
(220.20): calcd. C 60.00, H 4.12; found C 59.94, H 4.19.
penoate (6b): Analogously formed as a 3:2 hydrazino/hydrazono
mixture (6b/6b’) by using 2-fluorophenylhydrazine[49,50] (5.0 g,
40 mmol) in the above procedure; 9.1 g (82%) after purification by
chromatography on silica. – 1H NMR: δ ϭ 9.42 (br. d, J ϭ 10.9 Hz,
0.6 H), 7.97 (br. s, 0.4 H), 7.55 (d, J ϭ 10.9 Hz, 0.6 H), 7.41 (td,
J ϭ 8.5, 1.5 Hz, 0.4 H), 7.11 (d, J ϭ 7.0 Hz, 0.4 H), 7.0 (m, 2 H),
6.9 (m, 1.2 H), 6.8 (m, 0.4 H), 6.40 (br. s, 0.6 H), 4.14 (qd, J ϭ 8.5,
1.0 Hz, 0.4 H), 3.82 (s, 1.2 H), 3.79 (s, 1.8 H). – The pure hydrazino
tautomer 6b (30%) crystallized from the mixture of 6b and 6b’ upon
trituration with pentanes; m.p. 102–104 °C (after sublimation). –
19F NMR: δ ϭ –60.5 (s, 3 F), –134.8 (m, 1 F). – MS (CI): m/z
(%) ϭ 296 (4) [Mϩ ϩ NH4], 279 (42) [Mϩ ϩ 1], 278 (19) [Mϩ], 112
(100). – C11H10F4N4O2 (278.20): calcd. C 47.49, H 3.62; found C
47.29, H 3.66.
Methyl 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazole-4-carboxylate (7b):
Prepared analogously from the hydrazino/hydrazono compound
6b/6b’ (5.6 g, 20 mmol); m.p. 75–77 °C (after sublimation); 2.9 g
1
(61%). – H NMR: δ ϭ 8.01 (d, J ϭ 2.5 Hz, 1 H), 7.54 (td, J ϭ
7.6, 1.5 Hz, 1 H), 7.5 (m, 1 H), 7.3 (m, 2 H), 3.88 (s, 3 H). – 19F
NMR: δ ϭ –121.9 (dd, J ϭ 22.0, 2.5 Hz), –122.3 (m). – MS (CI):
m/z (%) ϭ 256 (7) [Mϩ ϩ NH4], 239 (100) [Mϩ ϩ 1], 238 (12)
[Mϩ], 207 (10). – C11H8F2N2O2 (238.19): calcd. C 55.47, H 3.39;
found C 55.39, H 3.16.
Methyl 5-Fluoro-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylate (7c):
Prepared analogously from the hydrazino/hydrazono compound 6c/
6c’ (5.9 g, 20 mmol); m.p. 64–65 °C (after sublimation); 2.0 g
1
(39%). – H NMR: δ ϭ 8.01 (d, J ϭ 2.5 Hz, 1 H), 7.6 (m, 1 H),
7.5 (m, 3 H), 3.88 (s, 3 H). – 19F NMR: δ ϭ –121.3 (t, J ϭ
2.5 Hz). – MS (CI): m/z (%) ϭ 257 (33), 256 (22), 255 (100) [Mϩ
ϩ 1], 254 (31) [Mϩ], 223 (47), 225 (17). – C11H8ClFN2O2 (254.65):
calcd. C 51.88, H 3.17; found C 51.97, H 3.17.
Methyl
3-N’-(2-Chlorophenyl)hydrazino-2-trifluoromethyl-2-pro-
penoate (6c): Use of 2-chlorophenylhydrazine[50,51] (5.7 g, 40 mmol)
in the above procedure again afforded a 3:2 hydrazino/hydrazono
mixture (6c/6c’); 9.4 g (80%) after purification by chromatography
Methyl
5-Fluoro-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carb-
1
on silica. – H NMR: δ ϭ 9.46 (br. d, J ϭ 10.9 Hz, 0.6 H), 8.21
oxylate (7d): Prepared analogously from the hydrazino/hydrazono
compound 6d/6d’ (7.3 g, 20 mmol); m.p. 86–88 °C (after sublima-
tion); 1.3 g (20%). – 1H NMR: δ ϭ 8.06 (d, J ϭ 2.4 Hz, 1 H), 7.53
(s, 2 H), 3.89 (s, 3 H). – 19F NMR: δ ϭ –122.1 (d, J ϭ 2.4 Hz). –
MS (CI): m/z (%) ϭ 328 (5), 327 (32), 326 (20), 325 (100), 324 (43),
323 (93), 322 (34) [Mϩ]. – C11H6Cl3FN2O2 (323.54): calcd. C 40.84,
H 1.87; found C 40.90, H 2.17.
(br. s, 0.4 H), 7.55 (d, J ϭ 11.0 Hz, 0.6 H), 7.44 (dd, J ϭ 8.5,
1.5 Hz, 0.4 H), 7.31 (dd, J ϭ 7.8, 1.5 Hz, 0.6 H), 7.25 (td, J ϭ 7.6,
1.5 Hz, 0.6 H), 7.22 (d, J ϭ 7.6 Hz, 0.8 H), 7.16 (d, J ϭ 7.3 Hz,
0.4 H), 6.9 (m, 1.2 H), 6.82 (td, J ϭ 7.6, 1.5 Hz, 0.4 H), 6.61 (br.
s, 0.6 H), 4.15 (qd, J ϭ 8.5, 1.0 Hz, 0.4 H), 3.83 (s, 1.2 H), 3.81 (s,
1.8 H). – The pure, crystalline hydrazino tautomer 6c (27%) was
isolated upon trituration of the tautomeric mixture of 6c and 6c’
with pentanes; m.p. 97–99 °C (after sublimation). – 19F NMR:
Methyl 5-Fluoro-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (7e): In
contrast to the four examples given above, the pyrazole 7e was pre-
pared without isolating and purifying the corresponding hydrazino/
hydrazono intermediate 6e. Thus, the acrylate 1 (3.7 g, 20 mmol),
2-pyridylhydrazine[52] (2.2 g, 20 mmol), and pyridine (4.9 mL, 4.8 g,
60 mmol) were dissolved in propan-2-ol (200 mL), the mixture was
heated under reflux for 2 h, and then concentrated to dryness. The
residue was purified by chromatography on silica by using an ethyl
acetate/hexanes mixture (1:3, v/v) as eluent; m.p. 96–98 °C (after
sublimation); 0.95 g (21%). – 1H NMR: δ ϭ 8.57 (dd, J ϭ 4.8,
1.8 Hz, 1 H), 7.97 (d, J ϭ 2.5 Hz, 1 H), 7.89 (ddd, J ϭ 8.2, 7.6,
1.8 Hz, 1 H), 7.76 (dd, J ϭ 8.2, 0.9 Hz, 1 H), 7.34 (ddd, J ϭ 7.6,
4.8, 0.9 Hz, 1 H), 3.89 (s, 3 H). – 19F NMR: δ ϭ –118.8 (d, J ϭ
2.5 Hz). – MS (CI): m/z (%) ϭ 222 (100) [Mϩ ϩ 1], 221 (8) [Mϩ],
190 (18). – C10H8FN3O2 (221.19): calcd. C 54.30, H 3.65; found C
54.48, H 3.71.
δ ϭ –60.5 (s). – MS (CI): m/z (%) ϭ 314 (6), 312 (15) [Mϩ
ϩ
NH4], 297 (33), 296 (16), 295 (100) [Mϩ ϩ 1], 294 (9) [Mϩ]. –
C11H10F3N2O2 (294.66): calcd. C 44.84, H 3.42; found C 44.51,
H 3.33.
Methyl 3-N’-(2,4,6-Trichlorophenyl)hydrazino-2-trifluoromethyl-2-
propenoate (6d): Use of 2,4,6-trichlorophenylhydrazine (8.5 g,
40 mmol) in the above procedure gave a 9:1 hydrazino/hydrazono
mixture (6d/6d’); 13.1 g (90%) after extraction and drying. – 1H
NMR: δ ϭ 9.43 (br. d, J ϭ 10.9 Hz, 0.9 H), 7.70 (d, J ϭ 10.9 Hz,
0.9 H), 7.59 (br. s, 0.1 H), 7.35 (s, 2.0 H), 6.46 (br. s, 0.9 H), 4.09
(quint., J ϭ 8.2 Hz, 0.1 H), 3.82 (s, 0.3 H), 3.76 (br. s, 2.7 H). –
The hydrazino tautomer 6d (77%) was obtained in a pure state
by precipitation from a concentrated methanol solution by adding
pentanes and subsequent recrystallization from methanol; m.p.
146–150 °C. – 19F NMR: δ ϭ –60.4 (s). – MS (CI): m/z (%) ϭ 368
(7), 367 (30), 366 (25), 365 (93), 364 (55), 363 (100) [Mϩ ϩ 1], 362
(37) [Mϩ]. – C11H8Cl3F3N2O2 (363.55): calcd. C 36.34, H 2.22;
found C 36.37, H 2.10.
Methyl 5-Anilino-1-phenyl-1H-pyrazole-4-carboxylate (8a): At 0 °C,
butyllithium (10 mmol) in hexanes (7 mL) followed by methyl 5-
fluoro-1-phenyl-1H-pyrazole-3-carboxylate (7a; 1.10 g, 5.0 mmol)
were added to a solution of aniline (0.91 mL, 0.93 g, 10 mmol) in
tetrahydrofuran (15 mL). After 1 h at 25 °C, the mixture was neut-
ralized with ethereal hydrogen chloride, then concentrated and ab-
sorbed on silica. Elution with an ethyl acetate/hexanes mixture (1:7,
v/v) afforded product 8a as colorless needles; m.p. 74–75 °C; 1.2 g
(84%). – 1H NMR: δ ϭ 7.97 (s, 1 H), 7.82 (br. s, 1 H), 7.45 (d, J ϭ
7.9 Hz, 2 H), 7.19 (t, J ϭ 7.9 Hz, 2 H), 7.11 (t, J ϭ 7.9 Hz, 1 H),
6.99 (t, J ϭ 7.9 Hz, 2 H), 6.81 (t, J ϭ 7.9 Hz, 1 H), 6.68 (d, J ϭ
7.9 Hz, 2 H), 3.85 (s, 3 H). – MS (CI): m/z (%) ϭ 294 (100) [Mϩ
ϩ 1], 293 (20) [Mϩ], 261 (48). – C17H15N3O2 (293.32): calcd. C
69.61, H 5.15; found C 69.74, H 4.97.
Exposure of solutions of the pure hydrazino tautomers 6 to trace
amounts of triethylamine led to rapid re-establishment of the hy-
drazino/hydrazono equilibria. The 6/6’ proportions thus obtained
were identical with those initially found (2:1, 3:2, 3:2, and 9:1 in
the case of compounds 6a, 6b, 6c, and 6d, respectively).
Methyl 5-Fluoro-1-phenyl-1H-pyrazole-4-carboxylate (7a): Potas-
sium carbonate (2.8 g, 20 mmol) was added to a solution of the
hydrazino/hydrazono derivative 6a/6a’ in propan-2-ol (200 mL).
The mixture was heated under reflux for 45 min and then concen-
trated to dryness. The residue was purified by chromatography on
826
Eur. J. Org. Chem. 2000, 823Ϫ828

Fluorine-Sacrificial Cyclizations as an Access to 5-Fluoropyrazoles
FULL PAPER
1
Methyl 5-p-Anisidino-1-phenyl-1H-pyrazole-4-carboxylate (8b):
(58%). – H NMR: δ ϭ 8.04 (br. s, 1 H), 7.66 (dd, J ϭ 7.9, 1.5 Hz,
Analogously, by using p-anisidine, product 8b was prepared and 2 H), 7.5 (m, 4 H), 7.4 (m, 2 H), 6.9 (m, 2 H), 3.81 (s, 3 H). – 19F
isolated; m.p. 94–96 °C; 1.2 g (74%). – 1H NMR: δ ϭ 7.93 (s, 1 H),
NMR: δ ϭ –127.5 (br. s). – MS (CI): m/z (%) ϭ 329 (1) [Mϩ
ϩ
7.84 (br. s, 1 H), 7.36 (d, J ϭ 7.4 Hz, 2 H), 7.16 (t, J ϭ 7.4 Hz, 2 NH4], 312 (100) [Mϩ ϩ 1], 311 (23) [Mϩ], 189 (15). – C17H14FN3O2
H), 7.10 (t, J ϭ 7.4 Hz, 1 H), 6.65 (d, J ϭ 9.0 Hz, 2 H), 6.52 (d, (311.32): calcd. C 65.59, H 4.53; found C 65.22, H 4.53.
J ϭ 9.0 Hz, 2 H), 3.86 (s, 3 H), 3.65 (s, 3 H). – MS (CI): m/z (%) ϭ
324 (100) [Mϩ ϩ 1], 323 (25) [Mϩ], 291 (33). – C18H17N3O2
(323.35): calcd. C 66.86, H 5.30; found C 67.05, H 5.00.
Acknowledgments
This work was financially supported by the Schweizerische Na-
tionalfond zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20-49’307-96).
5-Fluoro-1-phenyl-1H-pyrazole-4-carboxylic Acid (9): The ester 7a
(4.4 g, 20 mmol) was dissolved in a 3:1 (v/v) mixture (200 mL) of
tetrahydrofuran and water and lithium hydroxide monohydrate
(0.84 g, 20 mmol) was added portionwise. The solution was kept at
25 °C for 2 h and then acidified with 2  hydrochloric acid to pH
[1]
´
M. Schlosser, B. Spahic, C. Tarchini, Angew. Chem. 1975, 87,
1. The thick white precipitate thus formed was collected by filtra-
tion, dried, and crystallized in the form of tiny needles from a mix-
ture of ethyl acetate and hexanes; m.p. 166–167 °C; 2.8 g (68%). –
1H NMR: δ ϭ 8.02 (d, J ϭ 2.5 Hz, 1 H), 7.65 (d, J ϭ 7.9 Hz, 2
H), 7.53 (t, J ϭ 7.9 Hz, 2 H), 7.43 (t, J ϭ 7.9 Hz, 1 H). – 19F
NMR: δ ϭ –121.6 (m). – MS (CI): m/z (%) ϭ 224 (3) [Mϩ ϩ NH4],
207 (100) [Mϩ ϩ 1], 206 (46) [Mϩ]. – C10H7FN2O2 (206.18): calcd.
C 58.26, H 3.42; found C 57.99, H 3.42.
346–347; Angew. Chem. Int. Ed. Engl. 1975, 14, 365–366.
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M. Schlosser, B. Spahic, Helv. Chim. Acta 1980, 63, 1223–1235.
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B. Spahic, T. M. T. Truong-Nguyen, M. Schlosser, Helv. Chim.
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B. Spahic, M. Schlosser, Helv. Chim. Acta 1980, 63, 1242–1256.
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5-Fluoro-N-1-diphenyl-1H-pyrazole-4-carboxamide (10a): (1-Benzo-
triazolyloxy)tripyrrolidinophosphonium hexafluorophosphate[44]
(2.6 g, 5.0 mmol), aniline hydrochloride (0.71 g, 5.5 mmol), and di-
isopropylethylamine (2.1 mL, 1.6 g, 13 mmol) were successively ad-
ded to a solution of the 5-fluoropyrazole acid 9 (1.0 g, 5.0 mmol)
in dichloromethane (25 mL). The resulting heterogeneous mixture
was stirred for 2 h at 25 °C, then the solvent was evaporated and the
crude product was purified by chromatography on silica by using a
1:4 (v/v) mixture of ethyl acetate and hexanes as eluent; m.p. 153–
[8]
[9]
[10]
[11]
`
ˆ
[12]
[13]
1
155 °C (from hexanes); 0.58 g (41%). – H NMR: δ ϭ 8.06 (d, J ϭ
[14]
2.7 Hz, 1 H), 7.7 (m, 2 H), 7.60 (d, J ϭ 7.4 Hz, 2 H), 7.54 (br. s, 1
H), 7.53 (t, J ϭ 7.9 Hz, 2 H), 7.43 (t, J ϭ 7.4 Hz, 1 H), 7.37 (t,
J ϭ 7.9 Hz, 2 H), 7.15 (t, J ϭ 7.4 Hz, 1 H). – 19F NMR: δ ϭ –
127.3 (br. s). – MS (CI): m/z (%) ϭ 299 (5) [Mϩ ϩ NH4], 282 (100)
[Mϩ ϩ 1], 281 (15) [Mϩ], 189 (16). – C16H12FN3O (281.29): calcd.
C 68.32, H 4.30; found C 68.35, H 4.20.
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[18]
[19]
5-Fluoro-N-2-methoxyphenyl-1-phenyl-1H-pyrazole-4-carboxamide
(10b): Prepared analogously as described above by using o-anisi-
dine hydrochloride (0.88 g, 5.5 mmol) instead of aniline hydro-
chloride; m.p. 109–111 °C (from ethyl acetate/hexanes); 0.57 g
[20]
[21]
1
(37%). – H NMR: δ ϭ 8.47 (dd, J ϭ 7.9, 1.5 Hz, 1 H), 8.30 (br.
s, 1 H), 8.06 (d, J ϭ 3.0 Hz, 1 H), 7.7 (m, 2 H), 7.53 (t, J ϭ 7.9 Hz,
2 H), 7.43 (t, J ϭ 7.9 Hz, 1 H), 7.08 (td, J ϭ 7.9, 1.5 Hz, 1 H),
7.00 (td, J ϭ 7.9, 1.5 Hz, 1 H), 6.91 (dd, J ϭ 7.9, 1.5 Hz, 1 H),
3.93 (s, 3 H). – 19F NMR: δ ϭ –127.5 (br. s). – MS (CI): m/z
(%) ϭ 312 (100) [Mϩ ϩ 1], 311 (15) [Mϩ], 189 (16). – C17H14FNO2
(311.31): calcd. C 65.59, H 4.53; found C 65.58, H 4.69.
[22]
[23]
[24]
[25]
[26]
[27]
[28]
5-Fluoro-N-3-methoxyphenyl-1-phenyl-1H-pyrazole-4-carboxamide
(10c): Prepared analogously as described above by using m-anisi-
dine hydrochloride (0.88 g, 5.5 mmol) instead of aniline hydro-
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1
(42%). – H NMR: δ ϭ 8.05 (d, J ϭ 2.7 Hz, 1 H), 7.7 (m, 2 H),
204.
7.5 (m, 3 H), 7.43 (tt, J ϭ 7.4, 1.2 Hz, 1 H), 7.39 (t, J ϭ 2.4 Hz, 1
H), 7.25 (t, J ϭ 4.1 Hz, 1 H), 7.04 (ddd, J ϭ 8.2, 1.8, 0.9 Hz, 1 H),
6.71 (ddd, J ϭ 8.2, 2.4, 0.9 Hz, 1 H), 3.82 (s, 3 H). – 19F NMR:
δ ϭ –127.3 (br. s). – MS (CI): m/z (%) ϭ 329 (3) [Mϩ ϩ NH4], 312
(100) [Mϩ ϩ 1], 311 (23) [Mϩ], 189 (15). – C17H14FN3O2 (311.31):
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Eur. J. Org. Chem. 2000, 823Ϫ828
827

J.-N. Volle, M. Schlosser
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828
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