1,3-dipolar cycloadditions of ethyl 2-diazo-3,3,3-trifluoropropanoate to alkynes and [1,5] sigmatropic rearrangements of the resulting 3H-pyrazoles: Synthesis of mono-, bis- and tris(trifluoromethyl)-substituted pyrazoles

Article abstract of DOI:10.1002/hlca.201400032

The 1,3-dipolar cycloadditions of ethyl 2-diazo-3,3,3-trifluoropropanoate with electron-rich and electron-deficient alkynes, as well as the van Alphen-Hüttel rearrangements of the resulting 3H-pyrazoles were investigated. These reactions led to a series of CF₃-substituted pyrazoles in good overall yields. Phenyl- and diphenylacetylene proved to be unreactive, but, at high temperature, the diazoalkane and phenylacetylene furnished a cyclopropene derivative. As expected, the 1,3-dipolar cycloaddition to the ynamine occurred much faster than those to electron-deficient alkynes. With one exception, all cycloadditions proceeded with excellent regioselectivities. The [1,5] sigmatropic rearrangement of the primary 3H-pyrazoles provided products with shifted acyl groups; products resulting from the migration of a CF₃ group were not detected. In agreement with literature reports, this rearrangement occurs faster with 3H-pyrazoles bearing electron-withdrawing substituents. Copyright

Full text of DOI:10.1002/hlca.201400032

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Helvetica Chimica Acta – Vol. 97 (2014)
1,3-Dipolar Cycloadditions of Ethyl 2-Diazo-3,3,3-trifluoropropanoate
to Alkynes and [1,5] Sigmatropic Rearrangements of the Resulting
3H-Pyrazoles: Synthesis of Mono-, Bis- and Tris(trifluoromethyl)-Substituted
Pyrazoles
by Daniel Gladow, Sebastian Doniz-Kettenmann, and Hans-Ulrich Reissig*
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin, Takustrasse 3, DE-14195 Berlin
(fax: þ 49(30)83855367; e-mail: hans.reissig@chemie.fu-berlin.de)
The 1,3-dipolar cycloadditions of ethyl 2-diazo-3,3,3-trifluoropropanoate with electron-rich and
electron-deficient alkynes, as well as the van AlphenꢀHꢀttel rearrangements of the resulting 3H-
pyrazoles were investigated. These reactions led to a series of CF3-substituted pyrazoles in good overall
yields. Phenyl- and diphenylacetylene proved to be unreactive, but, at high temperature, the diazoalkane
and phenylacetylene furnished a cyclopropene derivative. As expected, the 1,3-dipolar cycloaddition to
the ynamine occurred much faster than those to electron-deficient alkynes. With one exception, all
cycloadditions proceeded with excellent regioselectivities. The [1,5] sigmatropic rearrangement of the
primary 3H-pyrazoles provided products with shifted acyl groups; products resulting from the migration
of a CF3 group were not detected. In agreement with literature reports, this rearrangement occurs faster
with 3H-pyrazoles bearing electron-withdrawing substituents.
Introduction. – Although rare in nature, the intriguing pharmacological proper-
ties1) and importance in agriculture [2] of pyrazoles, five-membered heterocycles with
two adjacent N-atoms, have raised great interest in such derivatives in the last decade
[3]. A general approach to functionalized pyrazoles consists of the addition of
hydrazine derivatives to 1,3-dicarbonyl compounds or other 1,3-bis-electrophiles [4].
For electronic reasons, this approach most often lacks satisfactory regioselectivity. On
the contrary, the 1,3-dipolar cycloadditions of diazoalkanes to alkenes or alkynes are
intrinsically more regioselective due to the increased electronegativity difference
between the C- and the N-atom of the 1,3-dipole [5 – 8]. It is well-known that 3H-
pyrazoles obtained by cycloadditions of disubstituted diazoalkanes undergo thermal
[1,5] sigmatropic rearrangements to aromatic 1H-pyrazoles, as discovered by van Al-
phen, and later investigated systematically by Hꢀttel et al. (Scheme 1) [6][9][10].
Despite the high abundance of fluorine in the Earthꢂs crust in form of inorganic
fluorides, natural organofluorine compounds are extremely rare [11]. In contrast, the
introduction of F into organic molecules, frequently as a CF3 group (for selected
reviews and recent original articles, see [12]) has most often a severe impact on their
biological, pharmacological, and agricultural profile [13]. Not surprisingly, three out of
five top-selling pharmaceuticals contain at least one F-atom, and the number of
compounds is steadily increasing [14]. For example, the blockbuster drug Celecoxib
1
)
For a review, see [1a]. For recent original reports, see [1b – 1d].
ꢃ 2014 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Scheme 1. Construction of Pyrazole Derivatives by [3 þ 2] Cycloadditions of Diazo Compounds to
Alkynes and Subsequent [1,5] Sigmatropic Rearrangement
(Celebrexꢄ) contains a pyrazole ring with a CF3 moiety which is essential for its
pharmacological activity (Fig.) [15]. AS-136A [16] and SC-560 [17] are other successful
drug candidates. Trifluoromethyl-substituted NH-pyrazoles and derivatives thereof
were also studied as mono- and bidentate ligands in transition-metal complexes [18].
Remarkably, 1,3-dipolar cycloadditions of easily available ethyl 2-diazo-3,3,3-
trifluoropropanoate (1; cf. Scheme 2) have so far not been reported, although they
should provide interestingly functionalized heterocycles. In connection with our
ongoing research on organofluorine compounds and our recent reports on the synthesis
of perfluoro-substituted donorꢀacceptor cyclopropanes [18][19], we were interested in
the reactivity of compound 1 as a 1,3-dipole for the preparation of selectively CF3-
substituted pyrazoles. We were also curious to learn how the strong inductive electron-
withdrawing effect of the CF3 group influences the reactivity pattern in comparison to
the well-investigated dimethyl diazomalonate [6]. We also wanted to study how the
subsequent [1,5] sigmatropic rearrangements of the resulting 3H-pyrazoles are effected
by the presence of one or more CF3 groups.
Results. – The reaction of neat ethyl 2-diazo-3,3,3-trifluoropropanoate (1) with
the electron-rich 1-(diethylamino)prop-1-yne (2) in equimolar amounts furnished in
3 h at 408 3H-pyrazole-3-carboxylate 3 in 50% yield as yellow oil (Scheme 2). The
constitution of 3 was deduced from the observed coupling constant of 1.2 Hz for
(MeCH2)2N in the 13C-NMR spectrum, which results from coupling to the adjacent CF3
group. Under the applied conditions, the formation of unknown side-products was
observed, and 1 was not fully consumed. The reaction proceeded more efficiently with a
slight excess (1.5 equiv.) of 2 in refluxing Et2O, cleanly affording product 3 as yellow oil
in 81% yield.
Figure. Drugs or drug candidates with CF3-substituted pyrazole units

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Scheme 2. Cycloaddition of Ethyl 2-Diazo-3,3,3-trifluoropropanoate (1) with 1-(Diethylamino)prop-1-
yne (2) and Subsequent [1,5] Sigmatropic Rearrangements
Heating of 3H-pyrazole-3-carboxylate 3 in refluxing toluene provided the expected
1H-pyrazole-1-carboxylate 4 in 70% yield. The rearranged product 4 was clearly
distinguished from its precursor 3 by comparison of the chemical shifts of the C¼O
C-atom in the 13C-NMR spectra. Interestingly, 4 shows fluorescence with an emission
at 451 nm. At this stage, the spectroscopic data do not rule out that 4 might have
undergone a second [1,5] sigmatropic rearrangement to isomeric pyrazole 5. To
eliminate this possibility, 4 was heated to 2408 to yield a colorless compound with small
but significant differences in the NMR spectra and without photoluminescent activity.
The obtained data are in agreement with structure 5. Deacylation of 5 proceeded
smoothly by treatment with Et2NH at room temperature and afforded 1H-pyrazole 6 in
90% yield.
Next, we studied the cycloadditions of ethyl 2-diazo-3,3,3-trifluoropropanoate (1)
with a series of electron-deficient alkynes. In detail, we investigated the influence of
alkoxycarbonyl vs. CF3 substitution at the alkyne regarding the reactivity, regioselec-
tivity, and the stability of products. Heating of 1 and dimethyl acetylenedicarboxylate
(7) to 808 in a sealed tube without solvent cleanly provided 1H-pyrazole-tricarboxylate
9 in 96% yield (Scheme 3). In this case, the van AlphenꢀHꢀttel rearrangement was
Scheme 3. Cycloaddition of Diazo Ester 1 to Dimethyl Acetylenedicarboxylate (7) and Subsequent
Reactions

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apparently faster than the preceding 1,3-dipolar cycloaddition; hence, the primary 3H-
pyrazole 8 was not isolated. The rearrangement of 9 to 1H-pyrazole-tricarboxylate 10
proceeded quantitatively at 1808, and deacylation of 10 with Et2NH at room
temperature smoothly provided 1H-pyrazole-dicarboxylate 11. After purification on
silica gel, the pure compound was isolated in 48% yield.
We next investigated the less electron-deficient methyl prop-2-ynoate (12) in order
to test its reactivity and regioselectivity. Due to the higher volatility of 12, diazo ester 1
was reacted with an excess of 12 (10 equiv.) under solvent-free conditions (Scheme 4).
At ambient temperature, the reaction required 22 d to be completed, yet at 808 1 was
fully consumed within 3 h. In both cases an identical mixture of products was obtained,
which was separated by column chromatography (CC). The initially formed 3H-
pyrazole-dicarboxylate 13 was obtained in 35% yield. Under the reaction conditions
employed, a minor amount of 13 underwent EtOCO-group transfer to the N-atom, and
subsequent deacylation led to 15% of pyrazole 14. Remarkably, a larger amount of 13
underwent [1,5] sigmatropic rearrangement of the EtOCO group to C(4), followed by
H-atom shift, leading to pyrazole derivative 15 in 32% yield. As expected, the
spectroscopic data of 15 were very similar to those of the almost identical compound 11.
Now we directed our attention to CF3-substituted alkynes. Under neat conditions,
ethyl 4,4,4-trifluorobut-2-ynoate (16) reacted with diazo ester 1 within 6 d at 758 to
quantitatively furnish a 75:25 mixture of the two regioisomeric N-EtOCO-substituted
pyrazoles 17 and 18 (Scheme 5). The constitutional assignment of the two isomers was
achieved by 19F-NMR spectroscopy: The two CF3 groups show two singlets for 17, but
two quadruplets with a coupling constant of 9.7 Hz for 18, evidencing to the proximity
Scheme 4. Cycloaddition of Diazo Ester 1 with Methyl Prop-2-ynoate (12)
Scheme 5. Reaction of Diazo Ester 1 with Ethyl 4,4,4-Trifluorobut-2-ynoate (16) and Subsequent
Reactions

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of these two moieties. As expected, the adduct of the 1,3-dipolar cycloaddition was not
detected by NMR spectroscopy. An attempt to separate 17 and 18 by CC on silica gel
led to partial deacylation and decomposition. Fortunately, deacylation of the crude
product mixture 17/18 with Et2NH proceeded smoothly and afforded a mixture of clean
pyrazoles, 19/20. This mixture was successfully separated by HPLC and afforded 19 and
20 in 61 and 15% yield, respectively, allowing a full characterization of the two isomers.
We then investigated the addition of diazo ester 1 to hexafluorobutyne 21. For a
better handling of 21, the reaction was not performed under neat conditions, but in
Et2O as the solvent in a sealed tube. The cycloaddition was slow, even employing
2 equiv. of 21, and complete consumption of 1 was detected by 19F-NMR spectroscopy
only after 10 d at 808 (Scheme 6). NMR Analysis of the crude material evidenced the
1
formation of the N-EtOCO-substituted pyrazole 22. The H-NMR spectrum revealed
the presence of an EtOCO group, the 13C-NMR spectrum indicated the connection of
the EtOCO group to a N-atom, and the 19F-NMR spectrum exhibited signals for three
different CF3 groups. There was no indication that the primary cycloaddition product
was still present. Attempts to purify the N-acylated pyrazole by CC or by distillation
failed, whereas deacylation with Et2NH led to an inseparable mixture of compound 23,
and the resulting carbamate by-product. Gratifyingly, immediate treatment of the
crude product 22 with NH2CH2CH2NH2 at room temperature, followed by an acidic
extraction and distillation, afforded the desired tris(trifluoromethyl)-substituted 1H-
pyrazole 23 in 76% overall yield.
It should be mentioned that two procedures for the preparation of 23 have already
been published. Atherton and Fields described a highly efficient 1,3-dipolar cyclo-
addition of diazotrifluoroethane with 21; however, it has to be kept in mind that the
mixture is potentially explosive if warmed too rapidly [20]. The alternative five-step
sequence recently reported by Gerus et al. allows preparation on larger scale; however,
in the crucial step toxic gases such as SF4 and HF are required [21]. In view of the
commercial availability of starting materials and the increased stability of diazo alkane
1 – compared to diazo compounds without electron-withdrawing groups – our approach
is a viable alternative to the reported procedures.
Alkyl diazoacetates were reported to react with phenylacetylene and diphenyl-
acetylene (24) in high yields [6][22]. Surprisingly, all our attempts to isolate pyrazoles
from the addition of 1 to phenylacetylene or 24 were unsuccessful. These alkynes
apparently do not undergo smooth 1,3-dipolar cycloadditions as desired but afforded
after 4 weeks at 808 complex mixtures. Ultrasonification, microwave irradiation, or
heating to 1108 did not alter the outcome. However, heating of 1 to 1808 in the presence
of 1 equiv. of 24 led to cyclopropene 25, probably by N2 extrusion of 1 and carbene
addition to alkyne 24 (Scheme 7) [23].
Scheme 6. Cycloaddition of Diazo Ester 1 with 1,1,1,4,4,4-Hexafluorobut-2-yne (21) and Subsequent
Deacylation

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Scheme 7. Cyclopropenation of 1,2-Diphenylacetylene (24) with Diazo Ester 1
For comparison, we briefly studied the reactions of diazo ester 1 with typical
electron-deficient and electron-rich alkenes. Stoichiometric amounts of neat dimethyl
fumarate (26) and 1 afforded after 7 d at 808 the 4,5-dihydro-1H-pyrazole-tricarbox-
ylate 27 in 71% yield (Scheme 8). The initially formed 4,5-dihydro-3H-pyrazole
tautomerizes to 27 that is formed as a single diastereoisomer. Under the conditions
employed, the thermodynamically more stable diastereoisomer should dominate,
presumably the compound with trans-configuration of the two alkoxycarbonyl groups.
Dimethyl maleate did not react with diazo ester 1 under these conditions.
Heating of neat diazo ester 1 with an excess of 1-(pyrrolidin-1-yl)cyclohexene (28)
at 808 for 5 d afforded hydrazone 29. CC on silica gel and subsequent HPLC
purification afforded the pure compound in 42% yield (Scheme 9). In principle, the
obtained azo-coupling product could also be existent as a hydrazone isomer of 29 with
the C¼N moiety in conjugation with the cyclohexane CO group [24]. The constitution
of 29 as depicted was evidenced by the downfield signal (d 115.5 ppm) of the C¼N
moiety in the 13C-NMR spectrum, which showed a typical 2J coupling of 35.2 Hz with
the adjacent CF3 group. For the alternative hydrazone tautomer, a similar chemical
shift for the C¼N moiety is to be expected, however, no comparable coupling to F-
atoms is possible. We assume the (E)-geometry for 29, which should be favored due to a
possible H-bond.
Scheme 8. Cycloaddition of Diazo Ester 1 with Dimethyl Fumarate (26)
Scheme 9. Azo Coupling of 1-(Pyrrolidin-1-yl)cyclohexene (28) and Diazo Ester 1

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Discussion. – The following aspects of our results should be discussed: i) the rate
and the regioselectivity of the 1,3-dipolar cycloadditions and ii) the facility and
selectivity of the [1,5] sigmatropic rearrangements of the resulting 3H-pyrazoles.
The rates of 1,3-dipolar cycloadditions are strongly influenced by electronic and
steric effects, and the balance between these two basic effects is often subtle [25]. The
reactions reported above demonstrate that ethyl 2-diazo-3,3,3-trifluoropropanoate (1)
reacts rapidly with the electron-rich 1-(diethylamino)prop-1-yne (2), but slower with
the strongly electron-deficient alkynes dimethyl acetylenedicarboxylate (7) and methyl
prop-2-ynoate (12). Although monoester 12 is less electron-deficient than diester 7, it is
also less hindered, and hence the cycloaddition is slightly faster. The reactions with
ethyl 4,4,4-trifluorobut-2-ynoate (16) and 1,1,1,4,4,4-hexafluorobut-2-yne (21) proceed
considerably slower, since these compounds are disubstituted, and only in 16 the
alkoxycarbonyl group acts as a strong acceptor. Compared to the alkoxycarbonyl
group, a CF3 group has apparently only a closely sufficient inductive electron-
withdrawing effect. Phenylacetylene and diphenylacetylene (24) did not participate in a
1,3-dipolar cycloaddition with diazo ester 1 due to the lack of electronic activation.
From these qualitative observations, the order of reactivity of alkynes for the
cycloaddition with diazo ester 1 can be estimated as: 2 > 12 > 7 > 16 ꢁ 21 >> 24. The
reactivity of dimethyl fumarate (26) towards 1 is comparable to that of alkyne 16 and
21.
Within the framework of the frontier-orbital model, diazo alkane 1 can be assigned
as Sustmann type-III dipole [26] being related to dimethyl diazomalonate [6]. For an
electron-rich alkyne such as 2, the HOMO(alkyne)ꢀLUMO(diazoalkane) interaction
is very dominant, whereas, for strongly electron-deficient alkynes, the LUMO(alky-
ne)ꢀHOMO(diazoalkane) interaction is more important. Dipolarophiles without
electronic activation react sluggish or not at all. Since 1 is slightly less electron-deficient
than dimethyl diazomalonate, its reactions with electron-deficient dipolarophiles
merely occur with moderate rate.
The cycloadditions of diazo ester 1 to alkynes 2 and 12 are perfectly regioselective
with the directions of addition being the same as reported in [6] for dimethyl
diazomalonate, which may again be explained by the frontier-orbital model considering
the orbital coefficients of the components in the dominant HOMOꢀLUMO
interaction. However, this simple model cannot correctly predict the ratio of
regioisomers formed in the cycloaddition of diazo ester 1 and alkyne 16 (Scheme 5).
A ratio of 3 :1 at 758 implies an energy difference of only 3.2 kJ/mol of the transition
states, leading to the two isomers. This small difference is beyond the scope of frontier-
orbital considerations and requires more sophisticated calculations including steric
interactions. Although a different diazoalkane was used, Shen and co-workers reported
a similar ratio of regioisomers in the addition of ethyl diazoacetate to methyl 4,4,4-
trifluorobut-2-ynoate providing a 5 :1 mixture of the two isomeric pyrazoles
(Scheme 10) [27].
The facility of 3H-pyrazoles to undergo a thermal van AlphenꢀHꢀttel rearrange-
ment strongly depends on the ability of the pyrazole core to stabilize a partial negative
charge and the ability of the migrating group to stabilize a partial positive charge2).
2
)
Calculations mentioned in [10] and refs. cit. therein.

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Scheme 10. Cycloaddition of Ethyl 2-Diazoacetate with Methyl 4,4,4-Trifluorobut-2-ynoate [27]
The most important observation with our compounds was the fact that a migration of
the CF3 group was never detected. Based on the literature reports and our results, we
can propose the following migratory tendency for thermal van AlphenꢀHꢀttel
rearrangements: CF3 < alkyl < Ph < COR << H [6][9][10].
The electron-donating effect of the Et2N group of 3H-pyrazole 3 clearly hampers
the migration of the EtOCO group, and hence the first [1,5] sigmatropic rearrangement
to give pyrazole 4 proceeded only at 1108 (Scheme 2). The second rearrangement to
pyrazole 5 starts from an aromatic compound, and, therefore, a higher activation
barrier has to be overcome requiring heating to 2408. In contrast, the [1,5] sigmatropic
rearrangement of electron-deficient 3H-pyrazole 8 was even faster than the cyclo-
addition (occurring at 808; see Scheme 3). The rearrangement of 4-unsubstituted 3H-
pyrazole 13 (Scheme 4) was in between these two cases, whereby the competitive
migration of the alkoxycarbonyl group to C(4) was preferred over the migration to the
N-atom.
Conclusions. – The 1,3-dipolar reactivity of 2-diazo-3,3,3-trifluoropropanoate (1)
towards alkynes and alkenes was studied and compared with that reported for related
electron-deficient diazoalkanes. With the exception of 1-(diethylamino)prop-1-yne (2)
and hexafluorobutyne (21), all additions proceeded efficiently without solvents. The
primary products were successfully isomerized and/or deacylated to provide the target
pyrazoles containing one, two, or three CF3 groups in good overall yields. Electroni-
cally unactivated alkynes did not afford the desired pyrazoles. At high temperature,
decomposition of 1 to the free carbene led to the cyclopropenation of diphenylace-
tylene (24) in moderate yield. Addition of neat 1 to dimethyl fumarate (26) afforded
the expected dihydropyrazole in good yield, whereas with 1-(pyrrolidin-1-yl)cyclohex-
ene (28) only azo coupling was observed. Overall, our experiments reveal that 2-diazo-
3,3,3-trifluoropropanoate (1) is an excellent 1,3-dipole providing a range of interesting
pyrazoles with CF3 groups. In addition, interesting mechanistic observations were
made concerning the cycloaddition step and the subsequent [1,5] sigmatropic re-
arrangements to 1H-pyrazoles.
Experimental Part
General. Reactions were generally performed under Ar in flame-dried flasks. Solvents and reagents
were added by syringes. Solvents were dried by standard procedures. Ethyl 2-diazo-3,3,3-trifluoropro-
panoate (1) [28] and N,N-diethylprop-1-yn-1-amine (2) [29] were prepared according to literature
procedures. Reagents were purchased and were used as received without further purification. Bulb-to-
bulb distillations were performed with a Bꢀchi glass oven (B-585). Column chromatography (CC): SiO2
(230 – 400 mesh; Merck or Fluka). Prep. HPLC: Nucleosil 50-5 column, Macherey-Nagel; 96 ml/min; UV

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detection at 254 nm. Yields refer to anal. pure samples. M.p.: Reichert apparatus Thermovar;
uncorrected. UV/VIS Spectra: Scinco S-3150 PDA spectrophotometer; quartz cuvettes (1 cm); maxima
(max.) in nm; molar extinction coefficients e [dm3/mol · cm] as log e; sh, shoulder. Photoluminescence
spectra (PL): JASCO FP-6500; quartz cuvettes (1 cm). IR Spectra: JASCO FT/IR-4100 spectrometer.
NMR Spectra: Bruker (AVIII 700) and JEOL (ECS 500, ECX 400, and Eclipse 500) instruments;
chemical shifts relative to Me4Si (d(H) 0.00), CDCl3 (d(H) 7.26; d(C) 77.2; d(F), frequency calibrated
lock with ꢂ 1 ppm deviation); all 13C-NMR spectra 1H- or 19F-decoupled; mc, centered multiplet;
coupling constants in Hz. HR-MS: Agilent 6210 (ESI-TOF) instrument. Elemental analyses:
PerkinElmer CHN-Analyzer 2400 and Vario EL Elemental Analyzer.
Ethyl 4-(Diethylamino)-5-methyl-3-(trifluoromethyl)-3H-pyrazole-3-carboxylate (3). Compound 1
(500 mg, 2.75 mmol) was added to a soln. of 2 (458 mg, 4.12 mmol) in Et2O (5 ml), and the resulting
mixture was stirred at reflux for 3 h. Et2O was removed under reduced pressure, and CC (SiO2; 15%
AcOEt in hexane) of the residue afforded 3 (650 mg, 81%). Yellow oil. UV/VIS (MeCN): max. 393
(3.89), 330 (sh, 3.39). IR (ATR): 3065 – 2750 (CꢀH), 1745 (C¼O), 1580 (C¼C), 1245, 1200, 1160, 1120,
1035 (CꢀF). 1H-NMR (400 MHz, CDCl3): 4.25 (q, J ¼ 7.2, MeCH2O); 3.42, 3.28 (2dq, J ¼ 14.2, 7.1,
2 MeCH2N); 2.48 (s, Me); 1.27 (t, J ¼ 7.2, MeCH2O); 1.14 (t, J ¼ 7.1, 2 MeCH2N). 13C-NMR (101 MHz,
CDCl3): 161.0 (q, J(C,F) ¼ 1.3, EtOCO); 152.9 (C(5)); 134.3 (q, J(C,F) ¼ 1.6, C(4)); 121.0 (q, J(C,F) ¼
283, CF3); 94.9 (q, J(C,F) ¼ 25.5, C(3)); 63.1, 13.8 (EtOCO); 46.6 (q, J(C,F) ¼ 1.2, Et2N); 13.6
(Et2N); 13.5 (Me). 19F-NMR (470 MHz, CDCl3): ꢀ 67.7 (s, CF3). HR-ESI-TOF-MS: 332.0998 ([M þ
K]þ, C12H18F3KN3Oþ2 ; calc. 332.0983). Anal. calc. for C12H18F3N3O2 (293.29): C 49.14, H 6.19, N
14.33; found: C 49.45, H 6.17, N 14.29.
Ethyl 4-(Diethylamino)-3-methyl-5-(trifluoromethyl)-1H-pyrazole-1-carboxylate (4). Compound 3
(284 mg, 0.968 mmol) was dissolved in toluene (8 ml) and stirred at 1108 for 6 h. Toluene was removed
under reduced pressure, and CC (SiO2; 15% AcOEt in hexane) of the residue afforded 4 (200 mg, 70%).
Pale-yellow liquid. UV/VIS (MeCN): max. 307 (sh, 3.52), 239 (3.87). PL (MeCN): max. 451. IR (ATR):
3085 – 2745 (CꢀH), 1765 (C¼O), 1505, 1475, 1440, 1370, 1340 (C¼C), 1295, 1245, 1190, 1130, 1030 (CꢀF).
1H-NMR (400 MHz, CDCl3): 4.50 (q, J ¼ 7.1, MeCH2O); 3.03 (q, J ¼ 7.2, 2 MeCH2N); 2.26 (s, Me); 1.44
(t, J ¼ 7.1, MeCH2O); 0.99 (t, J ¼ 7.2, 2 MeCH2N)). 13C-NMR (101 MHz, CDCl3): 152.3 (C(3)); 148.6
(EtOCO); 137.2 (q, J(C,F) ¼ 1.6, C(4)); 126.9 (q, J(C,F) ¼ 39.5, C(5)); 119.9 (q, J(C,F) ¼ 269, CF3); 64.9,
13.6 (EtOCO); 47.5 (q, J(C,F) ¼ 1.5, Et2N); 14.0 (Et2N); 12.7 (Me). 19F-NMR (471 MHz, CDCl3): ꢀ 57.9
(s, CF3). HR-ESI-TOF-MS: 316.1264 ([M þ Na]þ, C12H18F3N3NaOþ2 ; calc. 316.1243). Anal. calc. for
C12H18F3N3O2 (293.29): C 49.14, H 6.19, N 14.33; found: C 49.26, H 6.37, N 14.27.
Ethyl 4-(Diethylamino)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-carboxylate (5). Neat
4
(134 mg, 0.457 mmol) was heated in a Bꢀchi apparatus to 2408 for 2 h. CC (SiO2; 10% AcOEt in
hexane) of the crude product afforded 5 (114 mg, 85%). Colorless oil. IR (ATR): 3075 – 2720 (CꢀH),
1765 (C¼O), 1290, 1170, 1135, 1110, 1090 (CꢀF). 1H-NMR (500 MHz, CDCl3): 4.52 (q, J ¼ 7.1,
MeCH2O); 2.93 (q, J ¼ 7.2, 2 MeCH2N); 2.49 (s, MeꢀC(5)); 1.47 (t, J ¼ 7.1, MeCH2O); 0.93 (t, J ¼ 7.2,
2 MeCH2N). 13C-NMR (101 MHz, CDCl3): 149.8 (C(5)); 144.3 (EtOCO); 143.6 (q, J(C,F) ¼ 37.6, C(3));
130.1 (C(4)); 120.9 (q, J(C,F) ¼ 270, CF3); 65.0, 14.0 (EtOCO); 49.0 (q, J(C,F) ¼ 0.9, Et2N); 14.3 (Et2N);
12.2 (Me). 19F-NMR (471 MHz, CDCl3): ꢀ 61.9 (s, CF3). HR-ESI-TOF-MS: 316.1266 ([M þ Na]þ,
C12H18F3N3NaOþ2 ; calc. 316.1243). Anal. calc. for C12H18F3N3O2 (293.29): C 49.14, H 6.19, N 14.33;
found: C 49.43, H 6.14, N 14.11.
N,N-Diethyl-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (6). At 08, Et2NH (40 mg,
0.55 mmol) was added to 5 (37 mg, 0.13 mmol), and the resulting mixture was stirred for 24 h at 218.
CC (SiO2; 10% AcOEt in hexane) of the crude product afforded 6 (25 mg, 90%). Colorless oil. IR
1
(ATR): 3600 – 2560 (NꢀH, CꢀH), 1470 (C¼C), 1275, 1120, 995 (CꢀF). H-NMR (500 MHz, CDCl3):
12.09 (s, NH); 2.94 (q, J ¼ 7.2, 2 MeCH2N); 2.24 (s, Me); 0.93 (t, J ¼ 7.2, 2 MeCH2N). 13C-NMR
(126 MHz, CDCl3): 139.6 (C(5)); 139.4 (q, J(C,F) ¼ 36.3, C(3)); 127.3 (C(4)); 122.0 (q, J(C,F) ¼ 269,
CF3); 49.4, 14.0 (Et2N); 9.6 (Me). 19F-NMR (471 MHz, CDCl3): ꢀ 60.4 (s, CF3). HR-ESI-TOF-MS:
222.1213 ([M þ H]þ, C9H15F3N3þ ; calc. 222.1213). Anal. calc. for C9H14F3N3 (221.22): C 48.86, H 6.38, N
18.99; found: C 48.74, H 6.43, N 18.88.
1-Ethyl 3,4-Dimethyl 5-(Trifluoromethyl)-1H-pyrazole-1,3,4-tricarboxylate (9). In a one-dram vial
were added 1 (1.00 g, 5.49 mmol) and 7 (0.717 g, 4.99 mmol). The vial was sealed with a Teflon-coated

Helvetica Chimica Acta – Vol. 97 (2014)
817
cap, and the mixture was stirred at 808 for 24 h. The excess of 1 was removed from the resulting dark-
yellow oil under reduced pressure (908/15 mbar) to afford 9 (1.56 g, 96%). Yellow solid. M.p. 78 – 808. IR
(ATR): 3110 – 2775 (CꢀH), 1790, 1750 (C¼O), 1270, 1210, 1160, 1030 (CꢀF). 1H-NMR (400 MHz,
CDCl3): 4.61 (q, J ¼ 7.1, MeCH2O); 3.96, 3.95 (2s, 2 MeO); 1.49 (t, J ¼ 7.1, MeCH2O). 13C-NMR
(101 MHz, CDCl3): 161.4, 159.8 (MeOCO); 147.0 (EtOCO); 142.6 (C(3)); 132.8 (q, J(C,F) ¼ 42.3, C(5));
122.3 (q, J(C,F) ¼ 2.7, C(4)); 118.3 (q, J(C,F) ¼ 271, CF3); 67.1, 13.9 (EtOCO); 53.6, 53.2 (MeOCO). 19F-
NMR (376 MHz, CDCl3): ꢀ 58.7 (s, CF3). HR-ESI-TOF-MS: 347.0465 ([M þ Na]þ, C11H11F3N2NaO6þ ;
calc. 347.0461). Anal. calc. for C11H11F3N2O6 (324.21): C 40.75, H 3.42, N 8.64; found: C 41.21, H 3.51, N
8.65.
1-Ethyl 4,5-Dimethyl 3-(Trifluoromethyl)-1H-pyrazole-1,4,5-tricarboxylate (10). In a round-bottom
flask with a condenser neat 7 (1.54 g, 4.75 mmol) was heated at 1808 for 3 h to afford 10 (1.54 g, > 99%).
Brown solid. Melting range: 60 – 708. IR (ATR): 3145 – 2785 (CꢀH), 1780, 1745 (C¼O), 1285, 1225, 1150,
1045 (CꢀF). 1H-NMR (400 MHz, CDCl3): 4.58 (q, J ¼ 7.1, MeCH2); 4.03, 3.89 (2s, 2 MeO); 1.48 (t, J ¼ 7.1,
MeCH2). 13C-NMR (101 MHz, CDCl3): 159.6, 159.4 (MeOCO); 147.3 (EtOCO); 143.8 (q, J(C,F) ¼ 39.8,
C(3)); 142.2 (C(5)); 119.3 (q, J(C,F) ¼ 271, CF3); 113.8 (C(4)); 67.1, 14.0 (EtOCO); 54.0, 52.9
(MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 63.0 (s, CF3). Anal. calc. for C11H11F3N2O6 (324.21): C
40.75, H 3.42, N 8.64; found: C 40.45, H 3.46, N 8.43.
Dimethyl 5-(Trifluoromethyl)-1H-pyrazole-3,4-dicarboxylate (11). At 08, Et2NH (730 mg,
9.98 mmol) was added to 10 (1.54 g, 4.75 mmol), and the resulting mixture was stirred for 30 min at
218. CC (SiO2; 50% AcOEt in hexane) of the crude product afforded 11 (572 mg, 48%). Orange oil. IR
(ATR): 3700 – 2580 (NꢀH, CꢀH), 1725 (C¼O), 1315, 1225, 1135, 1000 (CꢀF). 1H-NMR (400 MHz,
CDCl3): 12.39 (s, NH); 3.95, 3.93 (2s, 2 MeO). 13C-NMR (101 MHz, CDCl3): 161.7, 158.3 (MeOCO);
142.5 (q, J(C,F) ¼ 40.0, C(5)); 135.0 (mc, C(3)); 120.0 (q, J(C,F) ¼ 270, CF3); 115.1 (q, J(C,F) ¼ 1.4,
C(4)); 53.5, 53.2 (MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 61.7 (s, CF3). HR-ESI-TOF-MS: 275.0266
([M þ Na]þ, C8H7F3N2NaOþ4 ; calc. 275.0250). Anal. calc. for C8H7F3N2O4 (252.15): C 38.11, H 2.80, N
11.11; found: C 38.35, H 2.80, N 11.28.
3-Ethyl 5-Methyl 3-(Trifluoromethyl)-3H-pyrazole-3,5-dicarboxylate (13), Methyl 3-(Trifluoro-
methyl)-1H-pyrazole-5-carboxylate (14), and 4-Ethyl 5-Methyl 3-(Trifluoromethyl)-1H-pyrazole-4,5-
dicarboxylate (15). In a one-dram vial were added 1 (101 mg, 0.555 mmol) and 12 (468 mg, 5.57 mmol).
The vial was sealed with a Teflon-coated cap, and the mixture was stirred at 808 for 3 h. After cooling to
r.t., CC (SiO2; 15% AcOEt in hexane) of the crude product afforded 13 (52 mg, 35%), 14 (16 mg, 15%),
and 15 (47 mg, 32%).
Data of 13. Colorless oil. IR (ATR): 3160 – 2775 (CꢀH), 1710 (C¼O), 1300, 1245, 1210, 1130, 1030
1
(CꢀF). H-NMR (400 MHz, CDCl3): 7.28 (q, J(H,F) ¼ 1.2, HꢀC(4)); 4.28 (q, J ¼ 7.1, MeCH2); 3.89 (s,
MeO); 1.32 (t, J ¼ 7.1, MeCH2). 13C-NMR (101 MHz, CDCl3): 163.8, 162.9 (EtOCO, MeOCO); 133.2
(C(5)); 132.3 (q, J(C,F) ¼ 6.5, C(4)); 122.8 (q, J(C,F) ¼ 272, CF3); 110.2 (q, J(C,F) ¼ 31.1, C(3)); 61.6,
14.1 (EtOCO); 53.4 (MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 61.8 (d, J(F,H) ¼ 1.2, CF3). HR-ESI-
TOF-MS: 289.0392 ([M þ Na]þ, C9H9F3N2NaO4þ ; calc. 289.0407).
Data of 14. Colorless oil. IR (ATR): 3500 – 2690 (NꢀH, CꢀH), 1715 (C¼O), 1310, 1290, 1250, 1145,
1125, 1020 (CꢀF). 1H-NMR (400 MHz, CDCl3): 11.75 (s, NH); 7.09 (s, HꢀC(4)); 3.97 (s, MeO). 13C-NMR
(176 MHz, CDCl3): 159.2 (MeOCO); 144.2 (q, J(C,F) ¼ 39.6, C(3)); 135.3 (C(5)); 120.7 (q, J(C,F) ¼ 269,
CF3); 107.5 (q, J(C,F) ¼ 2.3, C(4)); 52.9 (MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 62.3 (s, CF3). HR-
ESI-TOF-MS: 193.0219 ([M ꢀ H]ꢀ, C6H4F3N2Oꢀ2 ; calc. 193.0230).
Data of 15. Colorless wax. Melting range: 28 – 408. IR (ATR): 3740 – 2700 (NꢀH, CꢀH), 1730
(C¼O), 1310, 1230, 1140, 1080 (CꢀF). 1H-NMR (400 MHz, CDCl3): 8.97 (s, NH); 4.39 (q, J ¼ 7.1,
MeCH2); 3.94 (s, MeO); 1.36 (t, J ¼ 7.1, MeCH2). 13C-NMR (101 MHz, CDCl3): 161.3 (MeOCO); 158.5
(EtOCO); 141.9 (q, J(C,F) ¼ 38.9, C(5)); 135.0 (C(3)); 120.1 (q, J(C,F) ¼ 270, CF3); 115.5 (q, J(C,F) ¼
1.2, C(4)); 62.5, 14.0 (EtOCO); 53.3 (MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 61.5 (s, CF3). HR-ESI-
TOF-MS: 305.0159 ([M þ K]þ, C9H9F3KN2O4þ ; calc. 305.0146). Anal. calc. for C9H9F3N2O4 (266.17): C
40.61, H 3.41, N 10.52; found: C 40.62, H 3.38, N 10.49.
Diethyl 3,5-Bis(trifluoromethyl)-1H-pyrazole-1,4-dicarboxylate (17) and Diethyl 4,5-Bis(trifluoro-
methyl)-1H-pyrazole-1,3-dicarboxylate (18). In a one-dram vial were added 1 (219 mg, 1.20 mmol) and 16
(200 mg, 1.20 mmol). The vial was sealed with a Teflon-coated cap, and stirring at 758 for 6 d afforded a

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Helvetica Chimica Acta – Vol. 97 (2014)
mixture 17/18 (419 mg, > 99%, 17/18 75 :25). Pale-yellow oil. IR (ATR): 3170 – 2790 (CꢀH), 1800, 1745
(C¼O), 1270, 1225, 1145, 1030 (CꢀF). HR-ESI-TOF-MS: 371.0460 ([M þ Na]þ, C11H10F6N2NaO4þ ; calc.
371.0437). Anal. calc. for C11H10F6N2O4 (348.20): C 37.94, H 2.89, N 8.05; found: C 37.70, H 2.92, N 8.09.
Data of 17. 1H-NMR (400 MHz, CDCl3): 4.61, 4.40 (2q, J ¼ 7.2, 2 MeCH2); 1.49, 1.36 (2t, J ¼ 7.2,
2 MeCH2). 13C-NMR (101 MHz, CDCl3): 159.4, 146.7 (2 EtOCO); 142.3 (q, J(C,F) ¼ 40.1, C(3)); 133.9
(q, J(C,F) ¼ 42.6, C(5)); 119.2 (q, J(C,F) ¼ 271, CF3); 119.1 (mc, C(4)); 118.1 (q, J(C,F) ¼ 272, CF3); 67.3,
63.2, 13.86, 13.76 (2 EtOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 58.3, ꢀ 62.4 (2s, 2 CF3).
1
Data of 18. H-NMR (400 MHz, CDCl3): 4.61, 4.44 (2q, J ¼ 7.2, 2 MeCH2); 1.48, 1.39 (2t, J ¼ 7.2,
2 MeCH2). 13C-NMR (101 MHz, CDCl3): 159.7, 146.9 (2 EtOCO); 144.4 (q, J(C,F) ¼ 2.2, C(3)); 119.9 (q,
J(C,F) ¼ 270, CF3); 117.8 (q, J(C,F) ¼ 272, CF3); 67.6, 63.1, 13.92, 13.81 (2 EtOCO); C(4) and C(5) were
not detected, probably due to low signal intensity or overlap with signals of the major isomer. 19F-NMR
(376 MHz, CDCl3): ꢀ 55.4, ꢀ 57.4 (2q, J ¼ 9.7, 2 CF3).
Ethyl 3,5-Bis(trifluoromethyl)-1H-pyrazole-4-carboxylate (19) and Ethyl 3,4-Bis(trifluoromethyl)-
1H-pyrazole-5-carboxylate (20). The mixture of 17/18 (419 mg, 1.20 mmol, 17/18 75 :25) was treated at 08
with Et2NH (88 mg, 1.20 mmol), and the mixture was stirred for 4 h at 218. CC (SiO2; 15% AcOEt in
hexane) of the resulting mixture and subsequent HPLC (10% AcOEt in hexane) afforded 19 (202 mg,
61%) and 20 (50 mg, 15%). Traces of AcOEt were removed from 19 at 958/10 mbar.
Data of 19. Colorless crystals. M.p. 90 – 928. IR (ATR): 3500 – 2750 (NꢀH, CꢀH), 1710 (C¼O), 1510,
1
1235, 1210, 1140, 1060 (CꢀF). H-NMR (400 MHz, CDCl3): 4.40 (q, J ¼ 7.2, MeCH2); 1.38 (t, J ¼ 7.2,
MeCH2); the NH signal was not detected. 13C-NMR (101 MHz, CDCl3): 159.9 (EtOCO); 140.9 – 139.8
(m, C(3), C(5)); 119.2 (q, J(C,F) ¼ 271, CF3); 112.3 (mc, C(4)); 62.7, 13.6 (EtOCO). 19F-NMR
(376 MHz, CDCl3): ꢀ 61.6 (s, CF3). HR-ESI-TOF-MS: 299.0239 ([M þ Na]þ, C8H6F6N2NaO2þ ; calc.
299.0226).
Data of 20. Colorless liquid. IR (ATR): 3490 – 2810 (NꢀH, CꢀH), 1730 (C¼O), 1235, 1135, 1050
(CꢀF). 1H-NMR (400 MHz, CDCl3): 4.49 (q, J ¼ 7.2, MeCH2); 1.42 (t, J ¼ 7.2, MeCH2); the NH signal was
not detected. 13C-NMR (101 MHz, CDCl3): 157.5 (EtOCO); 141.5 (q, J(C,F) ¼ 39.6, C(3)); 135.4 (C(5));
120.5, 119.7 (2q, J(C,F) ¼ 269, 270, CF3); 112.6 (q, J(C,F) ¼ 41.7, C(4)); 63.6, 13.9 (EtOCO). 19F-NMR
(376 MHz, CDCl3): ꢀ 55.3 (q, J ¼ 7.6, CF3); ꢀ 61.7 (q, J ¼ 7.4, CF3). HR-ESI-TOF-MS: 299.0239 ([M þ
Na]þ, C8H6F6N2NaOþ2 ; calc. 299.0226).
3,4,5-Tris(trifluoromethyl)-1H-pyrazole (23). In a flask equipped with a J. Young PTFE valve, 1
(500 mg, 2.75 mmol) was dissolved in dry Et2O (30 ml). Compound 21 (890 mg, 5.49 mmol) was
condensed into the soln. at ꢀ 1968. After warming to 218 the soln. was stirred at 808 for 10 d. At 218,
excess of 21 was evaporated, NH2CH2CH2NH2 (165 mg, 2.75 mmol) was added at 08, and the soln. was
stirred for 4 h at 218. The mixture was diluted with Et2O (200 ml) and washed with 1m HCl soln. (2 ꢃ
100 ml). After separation, the org. layer was washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The crude product (780 mg, > 99%) was pure according to NMR spectroscopy.
Bulb-to-bulb distillation (140 – 1508/0.1 mbar) afforded 23 (568 mg, 76%). Colorless oil. 1H-NMR
(400 MHz, CDCl3): 11.63 (br. s, NH). 13C-NMR (101 MHz, CDCl3): 138.1 (mc, C(3), C(5)); 119.9 (q,
J(C,F) ¼ 269, F3CꢀC(4)); 118.7 (q, J(C,F) ¼ 271, F3CꢀC(3), F3CꢀC(5)); 111.1 (mc, C(4)). 19F-NMR
(376 MHz, CDCl3): ꢀ 55.7 (mc, F3CꢀC(4)); ꢀ 61.0 (br. s, F3CꢀC(3), F3CꢀC(4)). The data agreed with
those reported in [21].
Ethyl 2,3-Diphenyl-1-(trifluoromethyl)cycloprop-2-ene-1-carboxylate (25). Compound 1 (1.00 g,
5.49 mmol) and 24 (0.980 g, 5.50 mmol) were heated to reflux for 24 h at an oil-bath temp. of 1808. After
cooling to r.t., CC (SiO2; 15% AcOEt in hexane) of the mixture afforded 25 (445 mg, 24%). Yellow wax.
Melting range: 60 – 798. IR (ATR): 3195 – 2780 (CꢀH), 1730 (C¼O), 1310, 1265, 1145, 1040 (CꢀF).
1H-NMR (400 MHz, CDCl3): 7.50 – 7.43 (m, 10 arom. H); 4.22 (q, J ¼ 7.1, MeCH2) 1.20 (t, J ¼ 7.1,
MeCH2OCO). 13C-NMR (101 MHz, CDCl3): 168.8 (COOEt); 130.4, 130.0, 129.2, 124.7 (Ph); 125.1 (q,
J(C,F) ¼ 277, CF3); 104.6 (q, J(C,F) ¼ 1.5, C(2), C(3)); 61.4, 14.0 (COOEt); 33.6 (q, J(C,F) ¼ 35.7, C(1)).
19F-NMR (376 MHz, CDCl3): ꢀ 63.0 (s, CF3). HR-ESI-TOF-MS: 355.0876 ([M þ Na]þ, C19H15F3NaOþ2 ;
calc. 355.0916).
5-Ethyl 3,4-Dimethyl 4,5-Dihydro-5-(trifluoromethyl)-1H-pyrazole-3,4,5-tricarboxylate (27). In a
one-dram vial were added 1 (200 mg, 1.10 mmol) and 26 (158 mg, 1.10 mmol). The vial was sealed with a
Teflon-coated cap, and the mixture was stirred at 808 for 7 d. The reaction was stopped despite of the

Helvetica Chimica Acta – Vol. 97 (2014)
819
incomplete consumption of 1; ca. 85% conversion according to 19F-NMR spectroscopy. Filtration (SiO2;
15% AcOEt in hexane, then 100% AcOEt) of the crude product afforded 27 (255 mg, 71%) as a single
diastereoisomer. Yellow viscous oil. IR (ATR): 3720 – 2700 (NꢀH, CꢀH), 1745, 1730, 1720 (C¼O), 1270,
1215, 1080 (CꢀF). 1H-NMR (400 MHz, CDCl3): 7.05 (s, NH); 4.42 – 4.39 (m, HꢀC(4)); 4.34, 4.24 (AB of
ABX3, JAX ¼ JBX ¼ 7.1, JAB ¼ 11.0, MeCH2); 3.84, 3.78 (2s, 2 MeOCO); 1.31 (X of ABX3, JAX ¼ JBX ¼ 7.1,
MeCH2). 13C-NMR (101 MHz, CDCl3): 167.3, 164.1, 160.9 (2 MeOCO, EtOCO); 139.6 (C(5)); 122.9 (q,
J(C,F) ¼ 283, CF3); 76.7 (q, J(C,F) ¼ 29.4, C(3)); 64.3, 13.7 (COOEt); 55.1 (q, J(C,F) ¼ 1.1, C(4)); 53.2,
52.8 (2 MeOCO). 19F-NMR (376 MHz, CDCl3): ꢀ 76.0 (s, CF3). HR-ESI-TOF-MS: 349.0629 ([M þ
Na]þ, C11H13F3N2NaOþ6 ; calc. 349.0618).
Ethyl 3,3,3-Trifluoro-2-[2-(2-oxocyclohexyl)hydrazinylidene]propanoate (29). In a one-dram vial
were added 1 (500 mg, 2.75 mmol) and 28 (1.25 g, 8.24 mmol). The vial was sealed with a Teflon-coated
cap, and the mixture was stirred at 808 for 5 d. After cooling to r.t., CC (SiO2; 15% AcOEt in hexane) of
the crude product and subsequent HPLC (12% AcOEt in hexane) afforded 29 (325 mg, 42%). Yellow
oil. IR (ATR): 3360 – 2800 (NꢀH, CꢀH), 1720, 1680 (C¼O), 1200, 1115, 1035 (CꢀF). 1H-NMR
(400 MHz, CDCl3): 11.30 (s, NH); 4.30 (q, J ¼ 7.1, MeCH2); 4.27 – 4.20 (m, CH); 2.57, 2.14, 1.98, 1.66 (4m,
3 CH2); 2.39 (tdd, J ¼ 13.7, 6.2, 0.9, 1 H of CH2); 1.78 (qt, J ¼ 13.2, 3.3, 1 H of CH2); 1.33 (t, J ¼ 7.1,
MeCH2)). 13C-NMR (101 MHz, CDCl3): 206.3 (C¼O); 161.2 (EtOCO); 121.7 (q, J(C,F) ¼ 270, CF3);
115.5 (q, J(C,F) ¼ 35.2, C¼N); 67.5, 14.0 (EtOCO); 61.1 (CH); 41.0, 34.8, 27.4, 23.8 (4 CH2). 19F-NMR
(376 MHz, CDCl3): ꢀ 64.5 (s, CF3). HR-ESI-TOF-MS: 279.0962 ([M ꢀ H]ꢀ, C11H14F3N2O3ꢀ ; calc.
279.0962).
We gratefully acknowledge support by the Deutsche Forschungsgemeinschaft (GRK 1582 ꢅFluorine
as Key Elementꢂ) and by Bayer HealthCare. We thank Prof. Dr. Dieter Lentz and Dr. Blazej Duda (Freie
Universitꢁt Berlin) for providing us with hexafluorobutyne, and Dr. Reinhold Zimmer for his assistance
during preparation of this manuscript.
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Received January 27, 2014